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Abstract
Tissue inhibitors of metalloproteinases (TIMPs) are classically known for regulating members of the metzincin protease family and are well recognized for their inhibitory effects in cancer development and progression. Despite their common evolutionary structure, the four TIMP proteins have unique properties and regulation, and produce distinct phenotypes when ablated. A comprehensive assessment of their function during tumorigenesis reveals substantial effects on cell proliferation, apoptosis, angiogenesis, invasion, and metastasis as well as a potential role in genomic instability. The TIMPs universally inhibit angiogenesis, invasion, and metastasis, but their specific effects on cell proliferation and apoptosis are both tissue specific and context dependent. They exert these effects in a metalloproteinase-dependent as well as metalloproteinase-independent manner. Knowledge gained from these biological studies provides a foundation for the full understanding of TIMP function in physiology and various pathologies as well as for the development of the next generation of therapeutic metalloproteinase inhibitors.
| Abbreviations | ||
| ADAM, | = | a disintegrin and metalloproteinase; |
| ADAMTS, | = | a disintegrin and metalloproteinase with thrombospondin-like motif; |
| AKT, | = | v-akt murine thymoma viral oncogene homolog 1; |
| ALT, | = | alternative lengthening of telomere; |
| ANG1, | = | angiopoietin-1; |
| ANG2, | = | angiopoietin-2; |
| AoSMC, | = | aortic smooth muscle cells; |
| AP-1, | = | activating protein 1; |
| AP-4, | = | activating enhancer-binding protein 4; |
| APC, | = | adenomatous polyposis coli protein; |
| ATM, | = | ataxia telangiectasia mutated; |
| Bax, | = | BCL2-associated X protein; |
| Bcl2, | = | B-cell CLL/lymphoma 2; |
| Bid, | = | BH3 interacting domain death agonist; |
| Bim, | = | BCL2 interacting protein; |
| BNIP1, | = | BCL2/adenovirus E1B 19kDa interacting protein 1; |
| BRCA, | = | breast cancer 1, early onset; |
| CAM assay, | = | chorioallantoic membrane assay; |
| cAMP, | = | cyclic adenosine monophosphate; |
| CHO, | = | Chinese hamster ovary cell; |
| c-MYC, | = | myc proto-oncogene protein; |
| CXCL12, | = | chemokine (C-X-C motif) ligand 12; |
| DCIS, | = | ductal carcimona in situ; |
| DMBA, | = | 7, 12-dimethylbenz [a] anthracene; |
| EC, | = | endothelial cells; |
| ECM, | = | extracellular matrix; |
| EGFR, | = | epidermal growth factor receptor; |
| EMMPRIN, | = | extracellular matrix metalloproteinase inducer; |
| ENU, | = | N-ethyl-N-nitrosourea; |
| EPA, | = | erythroid potentiating activity; |
| ERK, | = | extracellular signal-regulated kinase; |
| ES cells, | = | embryonic stem cells; |
| ETS, | = | E-Twenty-Six family of transcription factors; |
| FAK, | = | focal adhesion kinase; |
| FAS, | = | TNF receptor superfamily, member 6; |
| FGF-2, | = | fibroblast growth factor 2; |
| FGF-R1, | = | fibroblast growth factor receptor 1; |
| HB-EGF, | = | heparin-binding epidermal growth factor; |
| HCC, | = | hepatocellular carcinoma; |
| HDMEC, | = | human dermal microvascular endothelial cells; |
| HEMVEC, | = | human endometrial microvascular endothelial cells; |
| HGF, | = | hepatocyte growth factor; |
| HMVEC, | = | human microvascular endothelial cells; |
| HPV16, | = | human papillomavirus 16; |
| HUVEC, | = | human umbilical vein endothelial cells; |
| ICAM-1, | = | intercellular adhesion molecule 1; |
| IDC, | = | invasive ductal carcinoma; |
| IGF, | = | insulin-like growth factor; |
| IGFBP-3, | = | insulin-like growth factor binding protein 3; |
| JNK, | = | jun N-terminal kinase; |
| KDR, | = | kinase-insert domain receptor also known as vascular endothelial growth factor receptor 2; |
| KO, | = | knockout; |
| LEF/TCF, | = | lymphoid enhancer factor/T cell factor (transcription factors); |
| MCP-3, | = | monocyte chemotactic protein 3; |
| MDA, | = | Monroe Dunaway Anderson Cancer Center; |
| MEF-2, | = | myocyte enhancer factor 2; |
| MKP1, | = | serine/threonine specific protein phosphatase; |
| MMP, | = | matrix metalloproteinases; |
| MMPI, | = | MMP inhibitor; |
| MMTV, | = | mouse mammary tumor virus; |
| MOAP1, | = | modulator of apoptosis 1; |
| MVEC, | = | microvascular endothelial cells; |
| NF-Il6, | = | nuclear factor for IL-6; |
| NF-κ B, | = | nuclear factor κ B; |
| NFKB2, | = | nuclear factor of kappa light polypeptide gene enhancer in B-cells 2; |
| NK cell, | = | natural killer cell; |
| Noxa, | = | pro-apoptotic member of the Bcl-2 protein family; |
| NSCLC, | = | Non-Small Cell Lung Cancer; |
| PCNA, | = | proliferating cell nuclear antigen; |
| PDGF, | = | platelet-derived growth factor; |
| PEA3, | = | polyomavirus enhancer activator 3; |
| PI3K, | = | phosphoinositide 3-kinase; |
| PKA, | = | protein kinase A; |
| PMA, | = | phorbol 12-myristate 13-acetate; |
| PTEN, | = | phosphatase and tensin homolog; |
| PVA, | = | polyvinyl alcohol; |
| RA, | = | rheumatoid arthritis; |
| Rb, | = | retinoblastoma protein; |
| Rac1b, | = | ras-related C3 botulinum toxin substrate 1 isoform b; |
| RECK, | = | reversion-inducing cysteine-rich protein with Kazal motifs; |
| SH-PTP1, | = | protein tyrosine phosphatase, non-receptor type 6; |
| Sp1, | = | selective promoter 1; |
| STASIS, | = | stress-or aberrant-signaling induced senescence; |
| TACE, | = | TNF-alpha converting enzyme; |
| TG, | = | transgenic; |
| TGFα, | = | transforming growth factor alpha; |
| TGF-β, | = | transforming growth factor beta; |
| TIMPs, | = | tissue inhibitors of metalloproteinases; |
| TNFα, | = | tumor necrosis factor alpha; |
| TNF-R1, | = | tumor necrosis factor receptor 1; |
| TNF-RII, | = | tumor necrosis factor receptor 2; |
| TNFRSF21, | = | tumor necrosis factor receptor superfamily, member 21; |
| TRADD, | = | tumor necrosis factor receptor-associated death domain; |
| TRAIL, | = | TNF-related apoptosis-inducing ligand; |
| TRAIL-RI, | = | tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor-1; |
| TYK, | = | tyrosine kinase; |
| VEGF, | = | vascular endothelial growth factor; |
| VSMC, | = | vascular smooth muscle cells; |
| WAP, | = | whey acidic protein; |
| WAF1, | = | wild-type p53-activated fragment 1; |
| Wnt, | = | wingless and Int signaling pathway. |
| Abbreviations | ||
| ADAM, | = | a disintegrin and metalloproteinase; |
| ADAMTS, | = | a disintegrin and metalloproteinase with thrombospondin-like motif; |
| AKT, | = | v-akt murine thymoma viral oncogene homolog 1; |
| ALT, | = | alternative lengthening of telomere; |
| ANG1, | = | angiopoietin-1; |
| ANG2, | = | angiopoietin-2; |
| AoSMC, | = | aortic smooth muscle cells; |
| AP-1, | = | activating protein 1; |
| AP-4, | = | activating enhancer-binding protein 4; |
| APC, | = | adenomatous polyposis coli protein; |
| ATM, | = | ataxia telangiectasia mutated; |
| Bax, | = | BCL2-associated X protein; |
| Bcl2, | = | B-cell CLL/lymphoma 2; |
| Bid, | = | BH3 interacting domain death agonist; |
| Bim, | = | BCL2 interacting protein; |
| BNIP1, | = | BCL2/adenovirus E1B 19kDa interacting protein 1; |
| BRCA, | = | breast cancer 1, early onset; |
| CAM assay, | = | chorioallantoic membrane assay; |
| cAMP, | = | cyclic adenosine monophosphate; |
| CHO, | = | Chinese hamster ovary cell; |
| c-MYC, | = | myc proto-oncogene protein; |
| CXCL12, | = | chemokine (C-X-C motif) ligand 12; |
| DCIS, | = | ductal carcimona in situ; |
| DMBA, | = | 7, 12-dimethylbenz [a] anthracene; |
| EC, | = | endothelial cells; |
| ECM, | = | extracellular matrix; |
| EGFR, | = | epidermal growth factor receptor; |
| EMMPRIN, | = | extracellular matrix metalloproteinase inducer; |
| ENU, | = | N-ethyl-N-nitrosourea; |
| EPA, | = | erythroid potentiating activity; |
| ERK, | = | extracellular signal-regulated kinase; |
| ES cells, | = | embryonic stem cells; |
| ETS, | = | E-Twenty-Six family of transcription factors; |
| FAK, | = | focal adhesion kinase; |
| FAS, | = | TNF receptor superfamily, member 6; |
| FGF-2, | = | fibroblast growth factor 2; |
| FGF-R1, | = | fibroblast growth factor receptor 1; |
| HB-EGF, | = | heparin-binding epidermal growth factor; |
| HCC, | = | hepatocellular carcinoma; |
| HDMEC, | = | human dermal microvascular endothelial cells; |
| HEMVEC, | = | human endometrial microvascular endothelial cells; |
| HGF, | = | hepatocyte growth factor; |
| HMVEC, | = | human microvascular endothelial cells; |
| HPV16, | = | human papillomavirus 16; |
| HUVEC, | = | human umbilical vein endothelial cells; |
| ICAM-1, | = | intercellular adhesion molecule 1; |
| IDC, | = | invasive ductal carcinoma; |
| IGF, | = | insulin-like growth factor; |
| IGFBP-3, | = | insulin-like growth factor binding protein 3; |
| JNK, | = | jun N-terminal kinase; |
| KDR, | = | kinase-insert domain receptor also known as vascular endothelial growth factor receptor 2; |
| KO, | = | knockout; |
| LEF/TCF, | = | lymphoid enhancer factor/T cell factor (transcription factors); |
| MCP-3, | = | monocyte chemotactic protein 3; |
| MDA, | = | Monroe Dunaway Anderson Cancer Center; |
| MEF-2, | = | myocyte enhancer factor 2; |
| MKP1, | = | serine/threonine specific protein phosphatase; |
| MMP, | = | matrix metalloproteinases; |
| MMPI, | = | MMP inhibitor; |
| MMTV, | = | mouse mammary tumor virus; |
| MOAP1, | = | modulator of apoptosis 1; |
| MVEC, | = | microvascular endothelial cells; |
| NF-Il6, | = | nuclear factor for IL-6; |
| NF-κ B, | = | nuclear factor κ B; |
| NFKB2, | = | nuclear factor of kappa light polypeptide gene enhancer in B-cells 2; |
| NK cell, | = | natural killer cell; |
| Noxa, | = | pro-apoptotic member of the Bcl-2 protein family; |
| NSCLC, | = | Non-Small Cell Lung Cancer; |
| PCNA, | = | proliferating cell nuclear antigen; |
| PDGF, | = | platelet-derived growth factor; |
| PEA3, | = | polyomavirus enhancer activator 3; |
| PI3K, | = | phosphoinositide 3-kinase; |
| PKA, | = | protein kinase A; |
| PMA, | = | phorbol 12-myristate 13-acetate; |
| PTEN, | = | phosphatase and tensin homolog; |
| PVA, | = | polyvinyl alcohol; |
| RA, | = | rheumatoid arthritis; |
| Rb, | = | retinoblastoma protein; |
| Rac1b, | = | ras-related C3 botulinum toxin substrate 1 isoform b; |
| RECK, | = | reversion-inducing cysteine-rich protein with Kazal motifs; |
| SH-PTP1, | = | protein tyrosine phosphatase, non-receptor type 6; |
| Sp1, | = | selective promoter 1; |
| STASIS, | = | stress-or aberrant-signaling induced senescence; |
| TACE, | = | TNF-alpha converting enzyme; |
| TG, | = | transgenic; |
| TGFα, | = | transforming growth factor alpha; |
| TGF-β, | = | transforming growth factor beta; |
| TIMPs, | = | tissue inhibitors of metalloproteinases; |
| TNFα, | = | tumor necrosis factor alpha; |
| TNF-R1, | = | tumor necrosis factor receptor 1; |
| TNF-RII, | = | tumor necrosis factor receptor 2; |
| TNFRSF21, | = | tumor necrosis factor receptor superfamily, member 21; |
| TRADD, | = | tumor necrosis factor receptor-associated death domain; |
| TRAIL, | = | TNF-related apoptosis-inducing ligand; |
| TRAIL-RI, | = | tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor-1; |
| TYK, | = | tyrosine kinase; |
| VEGF, | = | vascular endothelial growth factor; |
| VSMC, | = | vascular smooth muscle cells; |
| WAP, | = | whey acidic protein; |
| WAF1, | = | wild-type p53-activated fragment 1; |
| Wnt, | = | wingless and Int signaling pathway. |
Notes
aEditor's note: References 156 to 187 are cited sequentially for the first time in this table, and are subsequently in the text, where appropriate.
aEditor's note: References 20 to 23 are cited sequentially for the first time in this table, and subsequently in the text, if appropriate.
aEditor's note: References 244 to 265 are cited for the first time in this table, and subsequently in the text, if appropriate.
aEditor's note: Reference 296 to 316 are cited sequentially for the first time in this table, and subsequently in the text, if appropriate.