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Tissue inhibitors of metalloproteinases and programmed cell death: Conundrums, controversies and potential implications
Abstract
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, which can synergistically degrade the major components of extracellular matrix (ECM). A key role in maintaining the balance between ECM deposition and degradation in several physio-pathological processes is carried out, through multiple biological functions, by four members of the tissue inhibitors of metalloproteinases (TIMPs) family. TIMP-1 and TIMP-2 are capable of inhibiting the activities of MMPs, can inhibit tumour growth, invasion and metastasis, exhibit growth factor-like activity, can inhibit angiogenesis and suppress programmed cell death (PCD) independently of the MMP-inhibitory activity. TIMP-3 is the only member which is tightly bound to ECM, inhibits TNF-alpha converting enzyme and induces PCD through the stabilization of TNF-alpha receptors on the cell surface. TIMP-4 plays a role in ECM homeostasis in a tissue-specific fashion and its overexpression induces PCD. The aim of this article is to review the exciting and intriguing literature on TIMPs, with special emphasis on their conflicting-paradoxical roles in PCD and their potential clinical usefulness.
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“Importantly, it inhibits tumor necrosis factor alpha-converting enzyme and induces apoptosis through the stabilization of tumor necrosis factor alpha receptors on the cell surface (42).”
From MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators (2008) · cites this paper as [42]
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Bashash, M., Shah, A. M., Hislop, G., Treml, M., Bretherick, K. L., Janoo-Gilani, R., Leach, S. R., Le, N. D., Bajdik, C. D., & Brooks-Wilson, A. R. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059157 · Cited by 25
Lizárraga, F., Maldonado, V., & Meléndez-Zajgla, J. (2004) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2004.02.004 · Cited by 25
Sørensen, N. M., Dowell, B. L., Stewart, K. D., Jensen, V., Larsen, L., Lademann, U. A., Murphy, G., Nielsen, H. J., nner, N. B. U., & Davis, G. J. (2005) · Tumor Biology · doi:10.1159/000085588 · Cited by 25
Metadata
- Authors
- Mannello, F., & Gazzanelli, G.
- Affiliations
- University of Urbino (IT)
- Corresponding author
- Mannello, F.
- ORCID
- Mannello, F.
- Venue
- Apoptosis
- Published
- 2001-12
- Volume
- 6
- Issue
- 6
- Pages
- 479-482
- ISSN
- 1360-8185 (ISSN-L)
- 1573-675X
- OpenAlex
- W309980051
- Cited by
- 185
- References
- 31
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 4 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 3 · 2015: 3 · 2014: 5 · 2013: 7 · 2012: 8
- FWCI
- 4.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springernature.com/gp/researchers/text-and-data-mining (tdm)
- www.springernature.com/gp/researchers/text-and-data-mining (vor)
- Locations
- APOPTOSIS (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutional Research information system (University of Urbino) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- tissue inhibitors of metalloproteinases, matrix metalloproteinases, programmed cell death, extracellular matrix degradation, TIMP-1, TIMP-2, TIMP-3, TIMP-4, TNF-alpha converting enzyme, angiogenesis inhibition, tumor invasion and metastasis
- MeSH terms
- Animals, Humans, Neoplasms, Tumor Necrosis Factor-alpha, Apoptosis, Tissue Inhibitor of Metalloproteinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
