Advanced search
Publication Cover
Emerging Therapeutic Targets Volume 4, 2000 - Issue 5
Journal homepage
32
Views
3
CrossRef citations to date
0
Altmetric
Review

Serine/threonine-specific protein phosphatases and cancer

Norbert Berndt Division of Hematology/Oncology, Childrens Hospital Los Angeles, University of Southern California School of Medicine, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA. [email protected]
Pages 581-608 | Published online: 25 Feb 2005

Bibliography

  • BARTEK J, LUKAS J, BARTKOVA J: Defects in cell cycle control and cancer. J Pathol (1999) 187:95–99.
  • FAHRAEUS R, FISCHER P, KRAUSZ E, LANE DP: New approaches to cancer therapies. J. Pathol (1999) 187:138–146.
  • MEIJER L, LECLERC S, LEOST M: Properties and potential applications of chemical inhibitors of cyclin-dependentkinases. Pharmacol. Ther. (1999) 82:279–284.
  • SAUSVILLE EA, ZAHAREVITZ D, GUSSIO R et al: Cyclin-dependent kinases: initial approaches to exploit a novel therapeutic target. Pharmacol Ther. (1999) 82:285–292.
  • SHAPIRO GI, HARPER JVV: Anticancer drug targets: cellcycle and checkpoint control. J an. Invest. (1999) 104:1645–1653.
  • SELLERS WR, FISHER DE: Apoptosis and cancer drug targeting. J. Clin. Invest. (1999) 104:1655–1661.
  • GIBSON NW, KENNEDY SP: Delivery of tumor suppressor genes to reverse the malignant phenotype. Adv. Drug Deliv. Rev. (1997) 26:119–133.
  • FOLKMAN J: Antiangiogenic gene therapy. Proc. Natl.Acad. Sci. USA (1998) 95:9064–9066.
  • KREBS EG, FISCHER EH: The phosphorylase b to a converting enzyme of rabbit skelet al muscle. Biochim. Biophys. Acta (1956) 20:150–157.
  • ••This paper put protein phosphorylation on the map andearned both authors the Nobel Prize in 1993.
  • FISCHER EH, GRAVES DJ, SNYDER CRITTENDEN ER, KREBS EG: Structure of the site phosphorylated in the phosphorylase b to a reaction. J Biol. Chem. (1959) 234:1698–1704.
  • •This paper reports the first ever determination of a phospho-rylation site, Serm in phosphorylase.
  • HUNTER T: Protein kinases and phosphatases: the Yin and Yang of protein phosphorylation and signaling. Cell (1995) 80:225–236.
  • HUNTER T:Phosphotyrosine -anew protein modifica-tion. Trends Biochem. Sci. (1982) 7:246–249.
  • CANTLEY LC, NEEL BG: New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc. Natl. Acad. Sci. USA (1999) 96:4240–4245.
  • HLOBILKOVA A, GULDBERG P, THULLBERG M, ZEUTHENJ, LUKAS J, BARTEK J: Cell cycle arrest by the PTEN tumor suppressor is target cell specific and may require protein phosphatase activity. Exp. Cell Res. (2000) 256:571–577.
  • MURRAY AW, HUNT T: The cell cycle-an introduction. WH Freeman & Co., New York, NY, USA (1993).
  • O'FARRELL PH, SU TT: Size control: cell proliferation does not equal growth. Curr. Biol. (1998) 8:R687–R689.
  • CONLON I, RAFF MC: Size control in animal develop-ment. Cell (1999) 96:235–244.
  • VAUX DL, KORSMEYER SJ: Cell death in development. Cell (1999) 96:245–254.
  • DAY SJ, LAWRENCE PA: Measuring dimensions: the regulation of size and shape. Development (2000) 127:2977–2987.
  • PARDEE AB: G1 events and regulation of cell prolifera-tion. Science (1989) 246:603–608.
  • ZETTERBERG A, LARSSON O, WIMAN KG: What is therestriction point? Curr. Opin. Cell Biol. (1995)7:835–842.
  • PLANAS-SILVA MD, WEINBERG RA: The restriction point and control of cell proliferation. Cum Opin. Cell Biol. (1997) 9:768–772.
  • HARTVVELL LH, KASTAN MB: Cell cycle control and cancer. Science (1994) 266:1821–1828.
  • PARDEE AB: Growth dysregulation in cancer cells. Adv. Cancer Res. (1994) 65:213–228.
  • SHERR CJ: Cancer cell cycles. Science (1996) 274:1672–1677.
  • PAULOVICH AG, TOCZYSKI DP, HARTWELL LH: When checkpoints fail. Cell (1997) 88:315–321.
  • COLLINS K, JACKS T, PAVLETICH NP: The cell cycle and cancer. Proc. Natl. Acad. Sci. USA (1997) 94:2776–2778.
  • ADAMS PD, KAELIN JR. WG: Negative control elements of the cell cycle in human tumors. CUIT. Opin. Cell Biol. (1998) 10: 791–797.
  • NIGG EA: Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle. BioEssays (1995) 17:471–480.
  • MORGAN DO: Cyclin-dependent kinases: engines, clocks and microprocessors. Ann. Rev. Cell Dev. (1997) 13:261–291.
  • CHIN L, POMERANTZ J, DEPINHO RA: The INK4a/ARF tumor suppressor: one gene-two products-two pathways. Trends Biochem. Sci. (1998) 23:291–296.
  • HENGST L, REED SI: Inhibitors of the Cip /Kip family. In: Cyclin Dependent Kinase (CDK) Inhibitors (Vol 227). Vogt PK, Reed SI (Eds.), Springer Verlag, Berlin, Germany (1998) :25–41.
  • MURRAY AW: Cyclin ubiquitination: the destructive end of mitosis. Cell (1995) 81:149–152.
  • HOYT MA: Eliminating all obstacles: regulated proteolysis in the eukaryotic cell cycle. Cell (1997) 91:149–151.
  • KOEPP DM, HARPER JW, ELLEDGE SJ: How the cyclin became a cyclin: regulated proteolysis in the cell cycle. Cell (1999) 97:431–434.
  • REED SI: G1/S regulatory mechanisms from yeast to man. In: Progress in Cell Cycle Research (Vol 2). Meijer L, Guidet S, Vogel L (Eds.), Plenum Press, New York, NY, USA (1996):15–27.
  • BARTKOVA J, LUKAS J, BARTEK J: Aberrations of the Gl-and G1 /S-regulating genes in human cancer. In: Progress in Cell Cycle Research (Vol 3). Meijer L, Guidet S, Philippe M (Eds.), Plenum Press, New York, NY, USA (1997):211–220.
  • WEINBERG RA: The retinoblastoma gene and gene product. Cancer Surveys (1992) 12:43–57.
  • RILEY DJ, LEE EYHP, LEE W-H: The retinoblastoma protein: more than a tumor suppressor. Ann. Rev. Cell Biol. (1994) 10:1–29.
  • BARTEK J, BARTKOVA J, LUKAS J: The retinoblastoma protein pathway and the restriction point. CUIT. Opin. Cell Biol. (1996) 8:805–814.
  • TAYA Y: RB kinases and RB-binding proteins: new points of view. Trends Biochem. Sci. (1997) 22:14–17.
  • MITTNACHT S: Control of pRB phosphorylation. Curr. Opin. Genet. Dev. (1998) 8:21–27.
  • KAELIN JR. WG: Functions of the retinoblastoma protein. BioEssays (1999) 21 :950–958.
  • GOODRICH DW, PING WANG N, QIAN Y-W, LEE EYHP, LEE W-H: The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle. Cell (1991) 67:293–302.
  • • This study is one of the first providing insights into the workings of the RB protein. Microinjection of several pRB varieties into tumour cells lacking function pRB was used to demonstrate that pRB regulates the transition from G1 into S phase. Thus, a truncated pRB that is much less phosphory-lated than the wild type causes a block in Gl, suggesting a potentially significant role for pRB dephosphorylation. However, this aspect of the findings is not discussed in the paper.
  • BATES S, PARRY D, BONETTA L, VOUSDEN KH, DICKSON C, PETERS G: Absence of cyclin D/cdk complexes in cells lacking functional retinoblastoma protein. Oncogene (1994) 9:1633–1640.
  • •This and the following paper [46] have an important implica-tion: that pRB is the only physiological substrate for Cdk4/cyclin D complexes.
  • LUKAS J, BARTKOVA J, ROHDE M, STRAUSS M, BARTEK J: Cyclin D1 is dispensable for G1 control in retinoblas-toma gene-deficient cells independently of cdk4 activity. Mol Cell. Biol. (1995) 15:2600–2611.
  • •See annotation for [45].
  • OHTSUBO M, THEODORAS AM, SCHUMACHER J, ROBERTS JM, PAGANO M: Human cyclin E, a nuclear protein essential for the Gi-to-S phase transition. Mol Cell. Biol. (1995) 15:2612–2624.
  • GENG Y, EATON EN, PICON M et al.: Regulation of cyclin E transcription by F2Fs and retinoblastoma protein. Oncogene (1996) 12:1173–1180.
  • TAKEMURA M, KITAGAWA T, IZUTA S et al.: Phosphory-lated retinoblastoma protein stimulates DNA polymerase a. Oncogene (1997) 15:2483–2492.
  • •A study that challenges the prevailing view that only unphosphorylated pRB has any activity.
  • KAMB A: Cyclin-dependent kinase inhibitors and human cancer. In: Cyclin Dependent Kinase (CDK) Inhibi-tors (Vol 227). Vogt PK, Reed SI (Eds.), Springer Verlag, Berlin, Germany (1998) :139–148.
  • KIYOKAWA H, KOFF A: Roles of cyclin-dependent kinase inhibitors: lessons from knockout mice. In: Cyclin Dependent Kinase (CDK) Inhibitors (Vol 227). Vogt PK, Reed SI (Eds.), Springer Verlag, Berlin, Germany (1998) :105–120.
  • LUKAS J, PARRY D, AAGAARD L et al.: Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature (1995) 375:503–506.
  • •This and the following paper [53] suggest that the Cdk inhibitor pl6Ink4 specifically blocks the initial phosphoryla-tion of pRB by Cdk4/cyclin D. Since Cdk4 has apparently no role other than phosphorylating pRB, any activity of pl6Ink4 would be wasted.
  • MEDEMA RH, HERRERA RE, LAM F, WEINBERG RA: Growth suppression by p16ink4 requires functional retinoblastoma protein. Proc. Natl. Acad. Sci. USA (1995) 92:6289–6293.
  • •See annotation for [52].
  • GIVOL I, GIVOL D, RULONG S, RESAU J, TSARFATY I, HUGHES SH: Overexpression of human p21wafliciP1 arrests the growth of chicken embryo fibroblasts transformed by individual oncogenes. Oncogene (1995) 11:2609–2618.
  • SGAMBATO A, ZHANG Y-J, CIAPARRONE M et al.: Overex-pression of p27Kip1 inhibits the growth of both normal and transformed human mammary epithelial cells. Cancer Res. (1998) 58:3448–3454.
  • SHEIKH MS, ROCHEFORT H, GARCIA M: Overexpression of p 21 WAF1 /CIP1 induces growth arrest, giant cell formation and apoptosis in human breast carcinoma cell lines. Oncogene (1995) 11:1899–1905.
  • WANG X, GOROSPE M, HUANG Y, HOLBROOK NJ: p27KiP1 overexpression causes apoptotic death of mammalian cells. Oncogene (1997) 15: 2991–2997.
  • FRIZELLE SP, GRIM J, ZHOU J et al: Re-expression ofp16INK4a in mesothelioma cells results in cell cycle arrest, cell death, tumor suppression and tumor regression. Oncogene (1998) 16:3087–3095.
  • DI LEONARDO A, LINKE SP, CLARKIN K, WAHL GM: DNA damage triggers a prolonged p53-dependent Gi arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev. (1994) 8:2540–2551.
  • HANNON GJ, BEACH D: p1 5 INK4B is a potential effector of TGF-I3-induced cell cycle arrest. Nature (1994) 371:257–261.
  • DATTO MB, LI Y, PANUS JF, HOWE DJ, XIONG Y, WANG X-F: Transforming growth factor 13 induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc. Natl. Acad. ScL USA (1995) 92:5545–5549.
  • KAMESAKI H, NISHIZAWA K, MICHAUD GY, COSSMAN J, KIYONO T: TGF-I31 induces the cyclin-dependent kinase inhibitor p27Kip1 mRNA and protein in murine B cells. J. Immunol. (1998) 160: 770–777.
  • WOLF BB, GREEN DR: Suicidal tendencies: apoptotic cell death by caspase family proteinases. J. Biol. Chem. (1999) 274:20049–20052.
  • EARNSHAW WC, MARTINS LM, KAUFMANN SH: Mammalian caspases: structure, activation, substrates and functions during apoptosis. Ann. Rev. Biochem. (1999) 68: 383–424.
  • KING KL, CIDLOWSKI JA: Cell cycle regulation and apoptosis. Ann. Rev. Physiol. (1998) 60:601–617.
  • EVAN GI, LITTLEWOOD T: A matter of life and cell death. Science (1998) 281:1317–1322.
  • LUNDBERG AS, WEINBERG RA: Control of the cell cycle and apoptosis. Eur. J. Cancer (1999) 35:531–539.
  • KIRSCHNER MW: Intracellular proteolysis. Trends Biochem. ScL (1999) 24:M42–M45.
  • SHEAFF RJ, GROUDINE M, GORDON M, ROBERTS JM, CLURMAN BE: Cyclin E-CDK2 is a regulator of p27Kip1. Genes Dev. (1997) 11:1464–1478.
  • •• These two papers [69, 70] introduce a new twist into the story. Phosphorylation of G1 inhibitors triggers their destruction by the ubiquitin pathway.
  • VLACH J, HENNECKE S, AMATI B: Phosphorylation-dependent degradation of the cyclin-dep en dent kinase inhibitor p27Kip1. EMBOJ (1997) 16: 5334–5344.
  • ••See annotation for [69].
  • CAYROL C, DUCOMMUN B: Interaction with cyclin-dependent kinases and PCNA modulates proteasome-dependent degradation of p21. Oncogene (1998) 17:2437–2444.
  • •Association with, or perhaps phosphorylation by, CDK2 triggers proteolytic degradation of p21.
  • ZHA J, HARADA H, YANG E, JOCKEL J, KORSMEYER SJ: Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-XL, Cell (1996) 87:619–628.
  • BLUME-JENSEN P, JANKNECHT R, HUNTER T: The Kit receptor promotes cell survival via activation of P13-kinase and subsequent Akt-mediated phosphory-lation of Bad on 5er136. Curr. Biol. (1998) 8:779–782.
  • CARDONE MH, ROY N, STENNICKE HR et al.: Regulation of cell death protease caspase-9 by phosphorylation. Science (1998) 282:1318–1321.
  • ••First demonstration that a caspase involved in the initiationof apoptosis can be directly inhibited by phosphorylation. This study implicates pro-survival PKB/Akt, a kinase that has risen to fame recently.
  • DOU QP, AN B: RB and apoptotic cell death. Front. BioscL (1998) 3:d419–430.
  • TAN X, WANG JYJ: The caspase-RB connection in cell death. Trends Cell Biol. (1998) 8:116–120.
  • HARBOUR JW, DEAN DC: Rb function in cell-cycle regulation and apoptosis. Nature Cell Biol. (2000) 2:E65–E67.
  • SHERR CJ, ROBERTS JM: CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. (1999) 13:1501–1512.
  • WEINBERG RA: E2F and cell proliferation: a world turned upside down. Cell (1996) 85:457–459.
  • JOHNSON DG: The paradox of E2F1: oncogene and tumor suppressor gene. Mol. Carcinog. (2000) 27:151–157.
  • SEWING A, WISEMAN B, LLOYD AC, LAND H: High-intensity raf signal causes cell cycle arrest mediated by p21ciPl. Mol. Cell. Biol. (1997)17:5588–5597.
  • WOODS D, PARRY D, CHERWINSKI H, BOSCH H, LEES E, MCMAHON M: Raf-induced proliferation or cell cycle arrest is determined by the level of raf activity with arrest mediated by p21ciP1. Mol. Cell. Biol. (1997) 17:5598–5611.
  • LEVINE AJ: p53, the cellular gatekeeper for growth and division. Cell (1997) 88:323–331.
  • HANAHAN D, WEINBERG RA: The hallmarks of cancer. Cell (2000) 100:57–70.
  • ••An outstanding review of a complex topic, discussing themajor alterations which are acquired by cancer cells before and during tumour progression. Anticipating major advances in our ability to map protein interactions in health and disease, the authors predict that cancer diagnosis and treatment will turn into a rational science on a par with chemistry or physics.
  • COHEN PTW: Novel protein serine/threonine phosphatases: variety is the spice of life. Trends Biochem. Sci. (1997) 22:245–251.
  • AGGEN JB, NAIRN AC, CHAMBERLIN R: Regulation of protein phosphatase-1. Chem. Biol. (2000) 7:R13–R23.
  • •This article is an up-to-date overview of the role of regula-tory and targeting subunits in PP1
  • BARFORD D, DAS AK, EGLOFF MP: The structure and mechanism of protein phosphatases: insights into catalysis and regulation. Ann. Rev. Biophys. Biomol. Struct. (1998) 27:133–164.
  • GOLDBERG J, HUANG H-B, KWON Y-G, GREENGARD P, NAIRN AC, KURIYAN J: Three-dimensional structure of the catalytic subunit of protein serine/threonine phosphatase-1. Nature (1995) 376:745–753.
  • EGLOFF M-P, COHEN PTW, REINEMER P, BARFORD D: Crystal structure of the catalytic subunit of human protein phosphatase 1 and its complex with tungstate. Mol. Biol. (1995) 254:942–959.
  • GRIFFITH JP, KIM JL, KIM EE et al: X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex. Cell (1995) 82:507–522.
  • DAS AK, COHEN PTW, BARFORD D: The structure of thetetratricopeptide repeats of protein phosphatase 5: implications for TPR-mediated protein-protein interactions. EMBO J. (1998) 17:1192–1199.
  • CHUN Y-S, SHIMA H, NAGASAKI K, SUGIMURA T, NAGAO M: PP172, a testis-specific protein serine/threonine-phosphatase Type 1 catalytic subunit, is associated with a protein having high sequence homology with the 78-kDa glucose-regulated protein, a member of the 70-kDa heat shock protein family. Proc. Nati Acad. Sci. USA (1994) 91:3319–3323.
  • OLIVIER CJ, SHENOLIKAR S: Physiologic importance of protein phosphatase inhibitors. Front. Biosci. (1998) 3 :d961–972.
  • LEE EYC, ZHANG L, ZHAO S et al: Phosphorylase phosphatase: new horizons for an old enzyme. Front. Biosci. (1999) 4:d270–285.
  • SCHONTHAL AH: Role of PP2A in intracellular signal transduction pathways. Front. Biosci. (1998) 3:d1262–1273.
  • VIRSHUP DM: Protein phosphatase 2A: a panoply of enzymes. Curr. Opin. Cell Biol. (2000) 1 2 :180–185.
  • ZOLNIEROWICZ S, FAVRE B, HEMMINGS BA: Carboxyl methylation-a new regulatory mechanism for an old enzyme, protein phosphatase 2A. Adv. Prot. Phosphatases (1994) 8:355–369.
  • BERNDT N: Protein dephosphorylation and the intracellular control of the cell number. Front. Biosci. (1999) 4:d22–42.
  • CONNELL-CROWLEY L, ELLEDGE SJ, HARPER JW: G1 cyclin-dependentkinases are sufficient to initiate DNA synthesis in quiescent human fibroblasts. Curr. (1998) 8:65–68.
  • CORI GT, CORI CF: The enzymatic conversion of phosphorylase ato b.J Biol. Chem. (1945) 158:321–332.
  • •The conversion of active phosphorylase a to inactive phosphorylase b is catalysed by so-called PR enzyme, which, much later, turned out to be PP1. Therefore, PP1 is the first interconverting enzyme ever discovered.
  • MEIJER L, PONDAVEN P, TUNG HYL, COHEN P, WALLACE RW: Protein phosphorylation and oocyte maturation. II. Inhibition of starfish oocyte maturation by intracel-lular microinjection of protein phosphatases 1 and 2A and alkaline phosphatase. Exp. Cell Res. (1986) 163: 489–499.
  • DOONAN JH, MORRIS NR: The bimG gene of Asp ergillus nidulans, required for completion of anaphase, encodes a homolog of mammalian phosphoprotein phosphatase 1. Cell (1989) 57:987–996.
  • ••This and the following two papers [103, 104], whichappeared in the same issue of Cell, nicely demonstrate the power of yeast and fungal genetics. Collectively, they establish that PP1-like enzymes are required for exit from M-phase. An interesting twist to this story is that the mutants described here were identified as PP1 by sequence homology to the mammalian PP1 that had been cloned 2 years earlier, rather than by biochemical assays. Thus, although significant, these papers provide no insight as to what the critical PP1 function in mitosis might be.
  • OHKURA H, KINOSHITA N, MIYATANI S, TODA T, YANAGIDA M: The fission yeast dis2+ gene required for chromosome disjoining encodes one of two putative Type 1 protein phosphatases. Cell (1989) 57:997–1007.
  • ••See annotation for [102].
  • BOOHER RN, BEACH D: Involvement of a Type 1 protein phosphatase encoded by bwsl±in fission yeast mitotic control. Cell (1989) 57:1009–1016.
  • ••See annotation for [102].
  • AXTON JM, DOMBRADI V, COHEN PTW, GLOVER DM: One of the protein phosphatase 1 isoenzymes in Drosophila is essential for mitosis. Cell (1990) 63:33–46.
  • •This and the next paper [106] confirm the results obtained in the previous three references [102-104] demonstrating that protein phosphatases play similar roles in the control of mitosis in higher eukaryotes.
  • FERNANDEZ A, BRAUTIGAN DL, LAMB NJC: Protein phosphatase Type 1 in mammalian cell mitosis: chromosomal localization and involvement in mitotic exit. J. Cell Biol. (1992) 116:1421–1430.
  • •In this study, microinjection of PP1 antibodies into cells released from G2 resulted in a late mitotic arrest. The paper also shows that PP1 translocates from the cytoplasm to the nucleus upon M-phase entry.
  • TAKAI A, BIALOJAN C, TROSCHKA M, RUEGG JC: Smooth muscle myosin phosphatase inhibition and force enhancement by black sponge toxin. FEBS Lett. (1987) 217:81–84.
  • •Through identifying the first natural toxin that functions as a phosphatase inhibitor, this paper was the basis for an avalanche of studies employing OA and other PP inhibitors to study protein phosphorylation-mediated events.
  • SUGANUMA M, FUJIKI H, SUGURI H et al.: Okadaic acid: an additional non-phorbol-12-tetr adecano ate-13-acetate-type tumor promoter. Proc. Natl. Acad. ScL USA (1988) 85:1768–1771.
  • •This article establishes that OA is a powerful tumour promoter in the mouse skin assay. Although its mechanism of action remained unknown at the time, OA does not, like phorbol esters, activate PKC.
  • COHEN P, COHEN PTVV: Protein phosphatases come of age. J Biol. Chem. (1989) 264:21435–21438.
  • •A review that comments on the recent progress in the field due to the discovery of small molecular weight PP inhibitors that helped to establish a role for phosphorylation in many more events than anticipated. This article also advances the hypothesis that PPs might act as tumour suppressors for the first time.
  • GRUPPUSO PA, MIKUMO R, BRAUTIGAN DL, BRAUN L: Growth arrest induced by transforming growth factor 131 is accompanied by protein phosphatase activation in human keratinocytes. J. Biol. Chem. (1991) 266:3444–3448.
  • LUDLOW JW, GLENDENING CL, LIVINGSTON DM, DECAPRIO JA: Specific enzymatic dephosphorylation of the retinoblastoma protein. Mol Cell. Biol. (1993) 13:367–372.
  • •Using cells released from nocodazole, the authors demonstrate that pRB dephosphorylation is initiated in anaphase and lasts until Gl. Since pRB dephosphorylation can be blocked by addition of I-1 or 1–2 to mitotic extracts, the authors conclude that pRB dephosphorylation is catalysed by a type-1 phosphatase.
  • ALBERTS AS, THORBURN AM, SHENOLIKAR S, MUMBY MC, FERAMISCO JR: Regulation of cell cycle progression and nuclear affinity of the retinoblastoma protein by protein phosphatases. Proc. Natl. Acad. ScL USA (1993) 90:388–392.
  • DURFEE T, BECHERER K, CHEN P-L et al.: The retinoblas-toma protein associates with the protein phosphatase Type 1 catalytic subunit. Genes Dev. (1993) 7:555–569.
  • •Using the yeast two-hybrid system, this paper demonstrates that PP la physically associates with pRB. Co-immunoprecipitation experiments confirm that this association persists from late M to S phase.
  • BERNDT N: Phosphorylation of protein phosphatase 1 by cyclin-dependent kinases: a novel mechanism for cell cycle control? Adv. Prot. Phosphatases (1995) 9:63–86.
  • •After short-term exposure to OA and calyculin A, inhibition of PP1, but not PP2A, results in hyperphosphorylation of pRB, most markedly in GO/G1, but also in M phase, suggesting that PP1-like activity might be required to keep pRB in a dephosphorylated, active state during GO/G1.
  • DOHADWALA M, DA CRUZ E SILVA EF, HALL FL et al.: Phosphorylation and inactivation of protein phosphatase 1 by cyclin-dependent kinases. Proc. Natl. Acad. ScL USA (1994) 91:6408–6412.
  • •The first demonstration that a PP catalytic subunit can be stoichiometrically inhibited by phosphorylation of a unique threonine residue (Thr32° in PP1 a). Since the kinase involved is a Cdk, this suggests a scenario in which inactiva-tion of PP1 might be necessary to permit transitions from one phase of the cell cycle to the next.
  • BERNDT N, DOHADWALA M, LIU CWY: Constitutively active protein phosphatase la causes Rb-dependent G1 arrest in human cancer cells. Curr. Biol. (1997) 7:375–386.
  • ••Circumventing the problems associated with overexpres-sion of PPs in mammalian cells, this study employs electro-injection to introduce PP1 proteins into synchronised human cells. The results suggests that inhibitory phosphory-lation of PP1 might be necessary to permit pRB phosphory-lation and exit from Gl. In addition, a distinct subpopulation of PP1 might be sufficient to induce apoptosis.
  • LIU CWY, WANG R-H, DOHADWALA M, SCHONTHAL AH, VILLA-MORUZZI E, BERNDT N: Inhibitory phosphoryla-tion of PP1 CC catalytic subunit during the G1 /S transi-tion. J Biol. Chem. (1999) 274:29470–29475.
  • •Confirms the hypothesis derived from the results of [116]. G1 /S phosphorylation of PP1 occurs only in cells that express functional pRB and, consistent with this finding, PP1 that is phosphorylated during G1 /S, is in a complex with pRB.
  • DRISCOLL B, TANG A, HU Y-H et al.: Discovery of a regulatory motif which controls the exposure of specific upstream CDK sites that determine both conformation and growth suppressing activity of pRb. J. Biol. Chem. (1999) 274:9463–9471.
  • •Employing a series of mutants, in which individual phosphorylation sites have been replaced by Ala, this paper identifies a number of pRB phosphorylation sites (Thr356, 5er807, 5er811 and Thr821) that are critically important for its conformation and its growth-suppressing function.
  • KRTOLICA A, KRUCHER NA, LUDLOW JW: Hypoxia-induced pRB hypo-phosphorylation results from downreg-ulation of CDK and upregulation of PP1 activities. Oncogene (1998) 17:2295–2304.
  • BRAUTIGAN DL, SUNWOO J, LABBE J-C, FERNANDEZ A, LAMB NJC: Cell cycle oscillation of phosphatase inhibitor-2 in rat fibroblasts coincident with p34cdc2 restriction. Nature (1990) 344:74–78.
  • KAKINOKI Y, SOMERS J, BRAUTIGAN DL: Multisite phosphorylation and the nuclear localization of phosphatase inhibitor 2-green fluorescent protein fusion protein during S phase of the cell growth cycle. J. Biol. Chem. (1997) 272:32308–32314.
  • YAMANO H, ISHII K, YANAGIDA M: Phosphorylation of dis2 protein phosphatase at the C-terminal cdc2 consensus and its potential role in cell cycle regula-tion. EMBO J (1994) 13:5310–5318.
  • •This paper confirms and extends the results reported in [115]. Fission yeast PP1 is also phosphorylated and inhibited by Cdkl in vitro and in vivo during the G2/M transition. In addition, overexpression of phosphorylation-resistant PP1 causes growth arrest.
  • SANGRADOR A, ANDRES I, EGUIRAUN A, LORENZO ML, ORTIZ JM: Growth arrest of Schizosaccharomyces pombe following overexpression of mouse Type 1 protein phosphatases. MoL Gen. Genet. (1998) 259:449–456.
  • •Important paper consistent with the results of [116].
  • KWON Y-G, LEE S-Y, CHOI Y, GREENGARD P, NAIRN AC: Cell cycle-dependent phosphorylation of mammalian protein phosphatase 1 by cdc2 kinase. Proc. Natl. Acad. Sci. USA (1997) 94:2168–2173.
  • •Along with [125], this is the first demonstration that PP1 is phosphorylated during mitosis in mammalian cells; this study employs phosphorylation site-specific antibodies to PPla.
  • PUNTONI F, VILLA-MORUZZI E: Protein phosphatase-1a, y1 and 8: changes in phosphorylation and activity in mitotic HeIa cells and in cells released from the mitotic block. Arch. Biochem. Biophys. (1997) 340:177–184.
  • •Published shortly after [124] and using isoform-specific antibodies, this study shows that all three PP1 isozymes undergo mitotic phosphorylation in vivo.
  • CHENG AY, DEAN NM, HONKANEN RE: Serine/threonine protein phosphatase Type 1-y1 is required for the completion of cytokinesis in human A549 lung carcinoma cells. J. Biol. Chem. (2000) 275:1846–1854.
  • OHKURA H, YANAGIDA M: S. pombe gene sds22+ essential for a midmitotic transition encodes a leucine-rich repeat protein that positively modulates protein phosphatase-1. Cell (1991) 64:149–157.
  • DINISCHIOTU A, BEULLENS M, STALMANS W, BOLLEN M: Identification of sds22 as an inhibitory subunit of protein phosphatase-1 in rat liver nuclei. FEBS Lett. (1997) 402:141–144.
  • NELSON DA, KRUCHER NA, LUDLOW JW: High molecular weight protein phosphatase Type 1 dephos-phorylates the retinoblastoma protein. J Biol. Chem. (1997) 272:4528–4535.
  • •This study implicates a PP1 regulatory subunit in the mitotic dephosphorylation of pRB.
  • PUNTONI F, VILLA-MORUZZI E: Association of protein phosphatase-18 with the retinoblastoma protein and reversible phosphatase activation in mitotic HeIa cells and in cells released from mitosis. Biochem. Biophys. Res. Commun. (1997) 235:704–708.
  • LORCA T, LABBÉ J-C, DEVAULT A et al.: Dephosphoryla-tion of cdc2 on threonine 161 is required for cdc2 kinase inactivation and normal anaphase. EMBO (1992) 11: 2381–2390.
  • PAULSON JR, PATZLAFF JS, VALLIS AJ: Evidence that the endogenous histone HI phosphatase in HeIa mitotic chromosomes is protein phosphatase 1, not protein phosphatase 2A. J Cell Sci. (1996) 109:1437–1447.
  • THOMPSON LJ, BOLLEN M, FIELDS AP: Identification of protein phosphatase 1 as a mitotic lamin phosphatase. J. Biol. Chem. (1997) 272:29693–29697.
  • ISHII K, KUMADA K, TODA T, YANAGIDA M: Require-ment for PP1 phosphatase and 20S cyclosome/APC for the onset of anaphase is lessened by the dosage increase of a novel gene sds2.7* EMBO J (1996) 15:6629–6640.
  • KLIX M-A, COHEN P, KARSENTI E: Cdc2 H1 kinase is negatively regulated by a Type 2A phosphatase in the Xenopus early embryonic cell cycle: evidence from the effects of okadaic acid. EMBO J. (1990) 9:675–683.
  • •Using cell-free extracts derived from Xenopus oocytes, this study uses the PP inhibitor OA in a sensible way to demonstrate that PP2A activity prevents the activation of Cdkl that is necessary for entry into mitosis.
  • CLARKE PR, HOFFMANN I, DRAETTA G, KARSENTI E: Dephosphorylation of cdc25-C by a Type 2A protein phosphatase: specific regulation during the cell cycle in Xenopus egg ex tracts. Mol. Biol. Cell (1993) 4:397–411.
  • •This and the next paper [137] provide a molecular explana-tion for the findings reported in [135]: PP2A dephosphory-lates and inhibits the dual-specificity phosphatase cdc25 whose activity is required to remove the phosphate groups from the N-terminal Thr and Tyr residues in Cdks.
  • LEE TH, TURCK C, KIRSCHNER MW: Inhibition of cdc2 activation by INII/PP2A. Mol. Biol. Cell (1994) 5:323–338.
  • •See annotation for [136].
  • KINOSHITA N, OHKURA H, YANAGIDA M: Distinct, essential roles of Type 1 and 2A protein phosphatases in the control of the fission yeast cell division cycle. Cell (1990) 63:405–415.
  • KAWABE T, MUSLIN AJ, KORSMEYER SJ: HOX11 interacts with protein phosphatases PP2A and PP1 and disrupts a G2 /M cell-cycle checkpoint. Nature (1997) 385:454–458.
  • VOORHOEVE PM, WATSON RJ, FARLIE PG, BERNARDS R, LAM EWF: Rapid dephosphorylation of p107 following UV irradiation. Oncogene (1999) 18:679–688.
  • LI H, ZHAO L-L, FUNDER JW, LIU J-P: Protein phosphatase 2Ainhibits nuclear telomerase activity in human breast cancer cells. J. Biol. Chem. (1997) 272:16729–16732.
  • GREIDER CW: Telomerase activity, cell proliferation and cancer. Proc. Natl. Acad. Sci. USA (1998) 95:90–92.
  • YAN Y, MUMBY MC: Distinct roles for PP1 and PP2A in phosphorylation of the retinoblastoma protein. J. Biol. Chem. (1999) 274:31917–31924.
  • JARAMILLO-BABB VL, SUGARMAN JL, SCAVETTA R et al.: Positive regulation of cdc2 gene activity by protein phosphatase Type 2A. J. Biol. Chem. (1996) 271:5988–5992.
  • LIN XH, WALTER J, SCHEIDTMANN K, OHST K, NEWPORT J, WALTER G: Protein phosphatase 2A is required for the initiation of chromosomal DNA replication. Proc. Nati Acad. Sci. USA (1998) 95:14693–14698.
  • PALLAS DC, SHAHRIK LK, MARTIN BL et al.: Polyoma small and middle T antigens and SV40 small T antigen form stable complexes with protein phosphatase 2A. Cell (1990) 60:167–176.
  • ••Together with the next three papers [147-149] this studyestablishes that PP2A is an intracellular receptor for several tumour antigens. In demonstrating that tumourigenesis via this route involves inhibition of PP2A, these studies present the most compelling evidence that PP2A might function as a tumour suppressor.
  • WALTER G, RUEDIGER R, SLAUGHTER C, MUMBY MC: Association of protein phosphatase 2A with polyoma virus medium tumor antigen. Proc. Natl. Acad. ScL USA (1990) 87:2521–2525.
  • •See annotation for [146].
  • YANG S-I, LICKTEIG RL, ESTES R, RUNDELL K, WALTER G, MUMBY MC: Control of protein phosphatases 2A by Simian virus 40 small-t antigen. Mol. Cell. Biol. (1991) 11:1988–1995.
  • •See annotation for [146].
  • SONTAG E, FEDOROV S, KAMABAYASHI C, ROBBINS D, COBB MH, MUMBY MC: The interaction of 5V40 small tumor antigen with protein phosphatase 2Astimulates the Map kinase pathway and induces cell prolifera-tion. Cell (1993) 75:887–897.
  • ••See annotation for [146].
  • CHEN J, MARTIN BL, BRAUTIGAN DL: Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation. Science (1992) 257:1261–1264.
  • •This paper, in combination with the follow-up study [151] suggests another pathway to malignant transformation that involves inhibition of PP2A, this time by covalent modifica-tion mediated by oncogenic tyrosine kinases.
  • CHEN J, PARSONS S, BRAUTIGAN DL: Tyrosine phospho-rylation of protein phosphatase 2A in response to growth stimulation and v-src transformation of fibroblasts. J. Biol. Chem. (1994) 269:7957–7962.
  • •See annotation for [150].
  • LI M, MAKKINJE A, DAMUNI Z: The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A. J. Biol. Chem. (1996) 271:11059–11062.
  • AL-MURRANI SWK, WOODGETT JR, DAMUNI Z: Expres-sion of I2PP2A, inhibitor of protein phosphatase 2A, induces c-Jun and AP-1 activity. Biochem. J. (1999) 341:293–298.
  • BAHARIANS Z, SCHONTHAL AH: Reduction of Ha-ras-induced cellular transformation by elevated expression of protein phosphatase 2A. Mol. Carcinog. (1999) 24:246–254.
  • •This paper is the first demonstration that a protein phosphatase interferes with oncogenic transformation. Using simple co-transfection, this paper demonstrates that PP2A counteracts ras-induced transformation. In the presence of PP2A, the number of foci is reduced by about 50%.
  • YOSHIDA T, TODA T, YANAGIDA M: A calcineurin-like gene ppb1+ in fission yeast: Mutant defects in cytoki-nesis, cell polarity, mating and spindle pole body positioning. J. Cell Sci. (1994) 107:1725–1735.
  • BAKSH S, DECAPRIO JA, BURAKOFF SJ: Calcineurin regulation of the mammalian G0/G1 checkpoint element, cyclin dependent kin ase 4. Oncogene (2000) 19:2820–2827.
  • FISCELLA M, ZHANG HL, FAN SJ et al.: Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. Proc. Natl. Acad. ScL USA (1997) 94:6048–6053.
  • GUTHRIDGE MA, BELLOSTA P, TAVOLONI N, BASILICO C: FIN13, a novel growth factor-inducible serine-threonine phosphatase which can inhibit cell cycle progression. Mol. Cell. Biol. (1997) 17:5485–5498.
  • ZUO Z, DEAN NM, HONKANEN RE: Serine/threonine protein phosphatase Type 5 acts upstream of p53 to regulate the induction of p21WAF1/Cip1 and mediate growth arrest. J. Biol. Chem. (1998) 273:12250–12258.
  • ZUO Z, URBAN G, SCAMMELL JG et al.: Serahr protein phosphatase Type 5 (PP5) is a negative regulator of glucocorticoid receptor-mediated growth arrest. Biochemistry (1999) 38:8849–8857.
  • BASTIANS H, PONSTINGL H: The novel human protein serine/threonine phosphatase 6 is a functional homologue of budding yeast Sit4p and fission yeast ppe1, which are involved in cell cycle reg-ulation. J. Cell ScL (1996) 109:2865–2874.
  • MARTIN SJ, GREEN DR: Protease activation during apoptosis: death by a thousand cuts? Cell (1995) 82:349–352.
  • KAWAMURA T, MATSUZAWA S, MIZUNO Y et al.: Different moieties of tautomycin involved in protein phosphatase inhibition and induction of apoptosis. Biochem. Pharmacol. (1998) 55:995–1003.
  • ••This paper is significant in that it reiterates a simple fact oflife. Just because one thing does two things at the same time, they are not necessarily related. In the phosphatase field, it is very popular to attribute any effects of OA and other PP inhibitors to phosphatase inhibition. This chemical tour de force demonstrates that some effects (in this case, apoptosis induction) can be divorced from their function as PP inhibi-tors and reinforces the idea that all inhibitors become less specific with time.
  • BAXTER GD, LAVIN MF: Specific protein dephosphory-lation in apoptosis induced by ionizing radiation and heat shock in human tumor lines. J. in/mum/ (1992) 148:1949–1954.
  • ••For the first time, evidence is presented to suggest thatdephosphorylation of a limited number of proteins might be involved in the induction, initiation or execution of apoptosis.
  • DUNIGAN DD, MADLENER JC: Serine/threonine protein phosphatase is required for tobacco mosaic virus-mediated programmed cell death. Virology (1995) 207:460–466.
  • JANICKE RU, WALKER PA, LIN XY, PORTER AG: Specific cleavage of the retinoblastoma protein by an ICE-like protease in apoptosis. EMBO J. (1996) 15:6969–6978.
  • CHEN W, OTTERSON GA, LIPKOWITZ S, KHLEIF SN, COXON AB, KAYE FJ: Apoptosis is associated with cleavage of a 5 kDa fragment from RB which mimics dephosphorylation and modulates E2F binding. Oncogene (1997) 14:1243–1248.
  • •Many laboratories have relied on Western blotting to assess the phosphorylation state of pRB, assuming that phosphory-lated pRB has an apparent molecular mass that is approxi-mately 5 kDa larger than that of unphosphorylated pRB. This paper demonstrates that, during apoptosis, pRB is subject to a proteolytic cleavage reaction that would go undetected in traditional pRB phosphorylation assays. Thus, to verify the molecular changes in pRB, more rigorous tools, such as 32P-labelling or antibodies to specific regions or pRB phosphorylation sites, are necessary.
  • TAN X, MARTIN SJ, GREEN DR, WANG JYJ: Degradation of retinoblastoma protein in tumor necrosis factor-and CD95-induced cell death. J Biol. Chem. (1997) 272:9613–9616.
  • BOUTILLIER A-L, TRINH E, LOEFFLER J-P: Caspase-dependent cleavage of the retinoblastoma protein is an early step in neuronal apoptosis. Oncogene (2000) 19:2171–2178.
  • DOU QP, AN B, WILL PL: Induction of a retinoblastoma phosphatase activity by anticancer drugs accompa-nies p53-independent G1 arrest and apoptosis. Proc. Natl. Acad. Sci. USA (1995) 92:9019–9023.
  • ••Without identifying the phosphatase involved, this paperpresents evidence that a drug (araC), which is already under investigation for use in cancer therapy, induces pRB dephosphorylation, thereby causing cell death.
  • MORANA SJ, WOLF CM, LI J, REYNOLDS JE, BROWN MK, EASTMAN A: The involvement of protein phosphatases in the activation of ICE/CED-3 protease, intracellular acidification, DNA digestion and apoptosis. J Chem. (1996) 271:18263–18271.
  • ••Using short-term exposure of cells to OA and calyculin A, the authors demonstrate that inhibition of phosphatases prevents pRB dephosphorylation and apoptosis.
  • KNUDSEN KE, WEBER E, ARDEN KC, CAVENEE WK, FERAMISCO JR, KNUDSEN ES: The retinoblastoma tumor suppressor inhibits cellular proliferation through two distinct mechanisms: inhibition of cell cycle progression and induction of cell death. Oncogene (1999) 18:5239–5245.
  • PUNTONI F, VILLA-MORUZZI E: Protein phosphatase-1 activation and association with the retinoblastoma protein in colcemid-induced apoptosis. Biochem. Biophys. Res. Commun. (1999) 266:279–283.
  • AYLLON V, MARTNEZ-A C, GARC1A A, CAYLA X, REBOLLO A: Protein phosphatase la is a ras-activated Bad phosphatase that regulates interleukin-2 deprivation-induced apoptosis. EMBO J. (2000) 19:2237–2246.
  • •Another study demonstrating the power of the two-hybrid system, which in this case helps to establish an important substrate for PPI that suggests a positive role for this enzyme in apoptosis.
  • MILLS JC, LEE VMY, PITTMAN RN: Activation of a PP2A-like phosphatase and dephosphorylation of tau protein characterize onset of the execution phase of apoptosis. J Cell Sci. (1998) 111:625–636.
  • DOBROWSKY RT, KAMIBAYASHI C, MUMBY MC, HANNUN YA: Ceramide activates heterotrimeric protein phosphatase 2A. J. Biol. Chem. (1993) 268:15523–15530.
  • HANNUN YA: The sphingomeylin cycle and the second messenger function of ceramide. J. Biol. Chem. (1994) 269:3125–3128.
  • ITO T, DENG X, CARR B, MAY WS: Bc1-2 phosphoryla-tion required for anti-apoptosis function. J. Biol. Chem. (1997) 272:11671–11673.
  • RUVOLO PP, DENG X, CARR BK, MAY WS: A functional role for mitochondrial protein kinase Ca in Bc12 phosphorylation and suppression of apoptosis. j Biol. Chem. (1998) 273:25436–25442.
  • DENG XM, ITO T, CARR B, MUMBY MC, MAY WS: Reversible phosphorylation of Bc12 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A. J Biol. Chem. (1998) 273:34157–34163.
  • •This paper establishes an important substrate for a phosphatase. The oncogenic and pro-survival bc1–2 protein is inactivated by PP2A. Together with [181], these studies suggest that PP2A may be instrumental in permitting the initiation of programmed cell death.
  • RUVOLO PP, DENG X, ITO T, CAR BK, MAY WS: Ceramide induces bc12 dephosphorylation via a mechanism involving mitochondrial PP2A. J. Biol. Chem. (1999) 274:20292–20300.
  • SANTORO MF, ANNAND RR, ROBERTSON MM et al.: Regulation of protein phosphatase 2A activity by caspase-3 during apoptosis. J. Biol. Chem. (1998) 273:13119–13128.
  • •This paper places a phosphatase downstream of a caspase. Proteolytic cleavage of a PP2A regulatory subunit increases the activity of the holoenzyme.
  • SHIBASAKI F, MCKEON F: Calcineurin functions in Ca2±-activated cell death in mammalian cells. J Cell Biol. (1995) 1 31:735–743.
  • WANG HG, PATHAN N, ETHELL IM et al.: Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science (1999) 284:339–343.
  • ASAI A, QIU JH, NARITA Y et al.: High level calcineurin activity predisposes neuronal cells to apoptosis.j Biol. Chem. (1999) 274:34450–34458.
  • YOUNG MRI: Protein phosphatases-1 and-2A regulate tumor cell migration, invasion and cytoskelet al organization. Adv. Exp. Med. Biol. (1996) 407:311–318.
  • JACKSON J, MEISINGER J, PATEL S et al.: Protein phosphatase-2A associates with the cytoskeleton to maintain cell spreading and reduced motility of nonmetastatic Lewis lung carcinoma cells: the loss of this regulatory control in metastatic cells. Invasion Metastasis (1998) 17:199–209.
  • BENEFIELD J, MEISINGER J, PETRUZZELLI GJ, YOUNG MRI: Endothelial cell response to human head and neck squamous cell carcinomas involves downreg-ula-tion of protein phosphatases-1/2A, cytoskelet al depolymerization and increased motility. Invasion Metastasis (1998) 17:210–220.
  • ITO A, KATAOKA TR, WATANABE M et al.: A truncated isoform of the PP2A B56 subunit promotes cell motility through paxillin phosphorylation. EMBOJ. (2000) 19:562–571.
  • WEIGMANN K, COHEN SM, LEHNER CF: Cell cycle progression, growth and patterning in imaginal discs despite inhibition of cell division after inactivation of Drosophila Cdc2 kinase. Development (1997) 124:3555–3563.
  • ••This and the following paper [191] have wide-rangingimplications. Blocking or accelerating cell cycle progression has no or very little effect on organ size, in this case the Drosophila wing. These results suggest that the regulation of cell growth overrides the regulation of cell proliferation.
  • NEUFELD TP, FLOR DE LA CRUZ A, JOHNSTON LA, EDGAR BA: Coordination of growth and cell division in the Drosophila wing. Cell (1998) 93:1183–1193.
  • ••See annotation for [190].
  • VERDU J, BURATOVICH MA, WILDER EL, BIRNBAUM MJ: Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB. Nature Cell Biol. (1999) 1:500–506.
  • ••This paper, together with [193], provides exciting insightsinto the regulation of cell size-as opposed to proliferation. PI3K-mediated activation of PKB is inhibited by PTEN. In addition, these results support the notion that cell prolifera-tion requires cell growth but not vice versa.
  • GOBERDHAN DCI, PARICIO N, GOODMAN EC, MLODZIK M, WILSON C: Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico /P13-kinase signaling pathway. Genes Dev. (1999) 13:3244–3258.
  • ••See annotation for [192].
  • EDGAR BA: From small flies come big discoveries about size control. Nature Cell Biol. (1999) 1:E191–E193.
  • FUJIKI H: Is the inhibition of protein phosphatase 1 and 2A activities a general mechanism of tumor promotion in human cancer development? Mol. Carcinog. (1992) 5:91–94.
  • WANG SS, ESPLIN ED, LI JL et al.: Alterations of the PPP2R1B gene in human lung and colon cancer. Science (1998) 282:284–287.
  • •Probably the first demonstration that a PP, albeit a regulatory subunit, acts as a tumour suppressor in the classical sense.
  • CALIN GA, DI IASIO MG, CAPRINI E et al: LOW frequency of alterations of the a (PPP2R1 A) and 13 (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms. Oncogene (2000) 19:1191–1195.
  • TAKAKURA S, KOHNO T, SHIMIZU K, OHWADA S, OKAMOTO A, YOKOTA J: Somatic mutations and genetic polymorphisms of the PPP1 R3 gene in patients with several types of cancers. Oncogene (2000) 19:836–840.
  • GOTZ J, PROBST A, EHLER E, HEMMINGS BA, KUES W: Delayed embryonic lethality in mice lacking protein phosphatase 2A catalytic subunit Ca. Proc. Natl. Acad. ScL USA (1998) 95:12370–12375.
  • ••The first gene knockout for a Ser/Thr-specific phosphatasedemonstrates that PP2A is essential for survival.
  • SOGAWA K, YAMADA T, MASAKI T et al.: Enhanced expression of catalytic subunits of protein phosphatase Type 1 and high S-phase fraction in liposarcoma. Res. Commun. Mol. Pathol. Pharmacol. (1994) 85:359–362.
  • YAMADA T, SOGAWA K, MASAKI T et al: Enhanced expression of catalytic subunit isoform PP1y1 of protein phosphatase Type 1 in malignant fibrous histiocytoma. Res. Commun. Mol. Pathol. Pharmacol (1994) 86:125–128.
  • SOGAWA K, YAMADA T, FUNAMOTO Y et al.: Selective increase in expression of isoform PP1-14 of type-1 protein phosphatase in chondrosarcoma cells. Res. Commun. Mol. Pathol Pharmacol. (1994) 86:375–378.
  • SOGAWA K, YAMADA T, OKA S et al.: Enhanced expres-sion of catalytic subunit isoform PP1-14 of protein phosphatase Type 1 associated with malignancy of osteogenic tumor. Cancer Lett. (1995) 89:1–6.
  • SOGAWA K, MASAKI T, MIYAUCHI A et al: Enhanced expression of PP1-14, a catalytic subunit isoform of protein phosphatase Type 1, in invasive ductal carcinoma of the breast. Cancer Lett. (1997) 112:263–268.
  • PEEPER DS, UPTON TM, LADHA MH et al.: Ras signalling linked to the cell-cycle machinery by the retinoblas-toma protein. Nature (1997) 386:177–180.
  • MITTNACHT S, PATERSON H, OLSON MF, MARSHALL CJ: Ras signalling is required for inactivation of the tumor suppressor pRb cell-cycle control protein. Curr. (1997) 7:219–221.
  • FOIANI M, LIBERI G, LUCCHINI G, PLEVANI P: Cell cycle-dependent phosphorylation and dephosphorylation of the yeast DNA polymerase a-primase B subunit. Mol Cell. Biol. (1995) 15:883–891.
  • WELLS NJ, FRY AM, GUANO F, NORBURY C, HICKSON ID: Cell cycle phase-specific phosphorylation of human topoisomerase IIa.j Biol. Chem. (1995)270:28357–28363.
  • HAGIWARA M, ALBERTS AS, BRINDLE P et al.: Transcrip-tional attenuation following cAMP induction requires PP-1-mediated dephosphorylation of CREB. Cell (1992) 70:105–113.
  • KITAGAWA M, HIGASHI H, SUZUKI-TAKAHASHI I et al.: Phosphorylation of F2F-1 by cyclin A-cdk2. Oncogene (1995) 10:229–236.
  • TRZEPACZ C, LOWY AM, KORDICH JJ, GRODEN J: Phosphorylation of the tumor suppressor adenoma-tous polyposis coli (APC) by the cyclin-dependent kinase p34`da. J. Biol. Chem. (1997) 272:21681–21684.
  • KUDOH T, ISHIDATE T, MORIYAMA M, TOYOSHIMA K, AKIYAMA T: G1 phase arrest induced by Wilms tumor protein WT1 is abrogated by cyclin/CDK complexes. Proc. Natl Acad. ScL USA (1995) 92 :4517–4521.
  • KIM J, LEE JM, BRANTON PE, PELLETIER J: Modification of EWS/WT1 functional properties by phosphorylation. Proc. Natl. Acad. ScL USA (1999) 96:14300–14305.
  • BALDI A, DELUCA A, CLAUDIO PP et al: The Rb2/pi30 gene product is a nuclear protein whose phosphoryla-tion is cell cycle regulated. J. Cell. Biochem. (1995) 59:402–408.
  • CHEN Y, FARMER AA, CHEN C-F, JONES DC, CHEN P-L, LEE W-H: BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner. Cancer Res. (1996) 56:3168–3172.
  • ANDREASSEN PR, LACROIX FB, VILLA-MORUZZI E, MARGOLIS RL: Differential subcellular localization of protein phosphatase-1a, y1 and 8 isoforms during both interphase and mitosis in mammalian cells. J. Cell Biol. (1998) 141:1207–1215.
  • HSU L-C, WHITE RL: BRCA1 is associated with the centrosome during mitosis. Proc. Natl. Acad. ScL USA (1998) 95:12983–12988.
  • APRELIKOVA ON, FANG BS, MEISSNER EG et al: BRCA1-associated growth arrest is RB-dependent. Proc. Natl. Acad. ScL USA (1999) 96:11866–11871.
  • CHENG AY, BALCZON R, ZUO Z, KOONS JS, WALSH AH, HONKANEN RE: Fostriecin-mediated G2-M-phase growth arrest correlates with abnormal centrosome replication, the formation of aberrant mitotic spindles and the inhibition of serine/threonine protein phosphatase activity. Cancer Res. (1998) 58:3611–3619.
  • ARBER N, DOKI Y, HAN EKH et al: Antisense to cyclin Di inhibits the growth and tumorigenicity of human colon cancer cells. Cancer Res. (1997) 57:1569–1574.
  • SAUTER ER, NESBIT M, LITWIN S, KLEIN-SZANTO AJP, CHEFFETZ S, HERLYN M: Antisense cyclin Di induces apoptosis and tumor shrinkage in human squamous carcinomas. Cancer Res. (1999) 59:4876–4881.

Websites

  • Websites of special note have been highlighted as:
  • •of interest
  • ••of considerable interest
  • http://my/webmd.com/content/dmk/dmk article 40055 Well-Connected. Non-small cell lung cancer.
  • •A website that provides medical information and advice primarily to patients. Continuously updated.
  • www.kinase.com/scerevisae S. cerevisiae protein kinases.
  • •A website set up by the biotech company Sugen that is dedicated to various aspects of protein kinases and phosphatases. Continuously updated.
  • http://flybase.bio.indiana.edu/genes/lk/function Function, location, process, & structure of gene product.
  • •A website dedicated to all things that matter to the Drosophila research community, including the Drosophila genome project. Continuously updated.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Order Reprints Request Corporate Permissions

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

Request Academic Permissions

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.