Tissue inhibitors of metalloproteinases and programmed cell death: conundrums, controversies and potential implications.
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.
Mannello
F
F
Istituto di Istologia e Analisi di Laboratorio, Facoltà di Scienze MFN, Università degli Studi, Urbino, Italy. mannello@uniurb.it
Gazzanelli
G
G
D000818:Animals; D017209:Apoptosis; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism* / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha