20
Views
15
CrossRef citations to date
0
Altmetric
Research Article

Interchangeable Roles for E2F Transcriptional Repression by the Retinoblastoma Protein and p27KIP1–Cyclin-Dependent Kinase Regulation in Cell Cycle Control and Tumor Suppression

, , ORCID Icon, &
Article: e00561-16 | Received 11 Oct 2016, Accepted 01 Nov 2016, Published online: 17 Mar 2023
 

ABSTRACT

The mammalian G1-S phase transition is controlled by the opposing forces of cyclin-dependent kinases (CDK) and the retinoblastoma protein (pRB). Here, we present evidence for systems-level control of cell cycle arrest by pRB-E2F and p27-CDK regulation. By introducing a point mutant allele of pRB that is defective for E2F repression (Rb1G) into a p27KIP1 null background (Cdkn1b−/−), both E2F transcriptional repression and CDK regulation are compromised. These double-mutant Rb1G/G; Cdkn1b−/− mice are viable and phenocopy Rb1+/− mice in developing pituitary adenocarcinomas, even though neither single mutant strain is cancer prone. Combined loss of pRB-E2F transcriptional regulation and p27KIP1 leads to defective proliferative control in response to various types of DNA damage. In addition, Rb1G/G; Cdkn1b−/− fibroblasts immortalize faster in culture and more frequently than either single mutant genotype. Importantly, the synthetic DNA damage arrest defect caused by Rb1G/G; Cdkn1b−/− mutations is evident in the developing intermediate pituitary lobe where tumors ultimately arise. Our work identifies a unique relationship between pRB-E2F and p27-CDK control and offers in vivo evidence that pRB is capable of cell cycle control through E2F-independent effects.

View publisher note:
Articles of Significant Interest Selected from This Issue by the Editors

ACKNOWLEDGMENTS

We thank Ashley Watson and Nathalie Bérubé for their technical expertise for pituitary sectioning and staining, as well as Charles Ishak, Gabe DiMattia, and Joe Mymryk for frequent discussions and experimental advice.

M.J.T. was funded by OGS, and M.J.T. and M.J.C. were members of the CIHR Strategic Training Program in Cancer Research (CaRTT). M.J.C. was a recipient of a CIHR MD/Ph.D. studentship. F.A.D. is the Wolfe Senior Fellow in Tumor Suppressor Genes. This work was funded by an operating grant from the CIHR (MOP-89765) to F.A.D.

Log in via your institution

Log in to Taylor & Francis Online

PDF download + Online access

  • 48 hours access to article PDF & online version
  • Article PDF can be downloaded
  • Article PDF can be printed
USD 61.00 Add to cart

Issue Purchase

  • 30 days online access to complete issue
  • Article PDFs can be downloaded
  • Article PDFs can be printed
USD 265.00 Add to cart

* Local tax will be added as applicable

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.