Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new member of the membrane-type matrix metalloproteinase (MT-MMP) subfamily tentatively named MT5-MMP was isolated from mouse brain cDNA library. It is predicted to contain (i) a candidate signal sequence, (ii) a propeptide region with the highly conserved PRCGVPD sequence, (iii) a potential furin recognition motif RRRRNKR, (iv) a zinc-binding catalytic domain, (v) a hemopexin-like domain, (vi) a 24-residue hydrophobic domain as a potential transmembrane domain, and (vii) a short cytosolic domain. Reverse transcriptase-polymerase chain reaction analysis of its transcripts indicates that MT5-MMP is expressed in a brain-specific manner consistent with the origin of its EST clone from cerebellum. It is also highly expressed during embryonic development at stages day 11 and 15. Like other MT-MMPs, MT5-MMP specifically activates progelatinase A when co-expressed in Madin-Darby canine kidney cells. Its ability to activate progelatinase A is dependent on its proteolytic activity since a mutation converting Glu to Ala in the zinc binding motif HE255LGH renders MT5-MMP inactive against progelatinase A. In contrast to other MT-MMPs, MT5-MMP tends to shed from cell surface as soluble proteinases, thus offering flexibility as both a cell bound and soluble proteinase for extracellular matrix remodeling processes. Taken together, these properties serve to distinguish MT5-MMP as a versatile MT-MMP playing an important role in extracellular matrix remodeling events in the brain and during embryonic development.
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PMID:Identification and characterization of the fifth membrane-type matrix metalloproteinase MT5-MMP. 1008 37

Liver regeneration depends on timely restoration of cellular mass while orchestrating structural matrix remodeling. Matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) are known to regulate the extracellular matrix (ECM) turnover and, more recently, the processing of growth factors and cytokines. We have previously demonstrated that TIMP-1 inhibits preneoplastic hepatocyte proliferation by attenuating growth factor bioavailability. In the present study, we examined the role of TIMP-1 in de novo hepatocyte cell division during liver regeneration. Comprehensive real-time reverse-transcriptase polymerase chain reaction analyses of regenerating livers revealed significant inductions in the messenger RNA of TIMP-1, TIMP-3, TIMP-4, MMP-2, MMP-9, MMP-13, MMP-14, and MMP-24, while MMP-15 expression was significantly reduced. Induction of TIMP-1 occurred during the peak of hepatocyte DNA synthesis. Studies using genetically altered mice revealed that TIMP-1 loss of function accelerated hepatocyte cell cycle progression. This finding was demonstrated by earlier expression of cyclin D1, proliferating cell nuclear antigen, and phosphorylated histone H3, which mark the G(1)-S, S, and M phase, respectively. Conversely, TIMP-1 gain of function delayed cell cycle progression. MMP activity was increased in the absence of Timp-1. Examination of hepatocyte growth factor (HGF), and its receptor Met, both of which provide a mitogenic signal for hepatocyte division, showed increased HGF activity in Timp-1(-/-)-regenerating livers. HGF is released from the ECM and is proteolytically processed to its active form. Active HGF was elevated in Timp-1(-/-) mice, leading to increased immunostaining of phosphorylated Met as well as activation of a downstream effector, p38. In conclusion, TIMP-1 is a novel negative regulator of HGF activity during liver regeneration.
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PMID:Metalloproteinase inhibitor TIMP-1 affects hepatocyte cell cycle via HGF activation in murine liver regeneration. 1572 41