Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.60 (caspase-7)
 920 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-small cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor (EGFR) responds to EGFR tyrosine kinase inhibitors such as erlotinib. However, secondary somatic EGFR mutations (e.g., T790M) confer resistance to erlotinib. BMS-690514, a novel panHER/vascular endothelial growth factor receptor (VEGFR) inhibitor described here, exerted antiproliferative and proapoptotic effects on NSCLC cell lines, with prominent efficacy on H1975 cells expressing the T790M mutation. In this model, BMS-690514 induced a G(1) cell cycle arrest, as well as ultrastructural hallmarks of apoptosis, mitochondrial release of cytochrome c, and activation of caspases involved in the intrinsic (e.g., caspase-2, caspase-3, caspase-7, and caspase-9), but not in the extrinsic (e.g., caspase-8), pathway. Caspase inhibition conferred partial protection against BMS-690514 cytotoxicity, pointing to the involvement of both caspase-dependent and caspase-independent effector mechanisms. Transcriptome analyses revealed the up-regulation of proapoptotic (e.g., Bim, Puma) and cell cycle inhibitory (e.g., p27(Kip1), p57(Kip2)) factors, as well as the down-regulation of antiapoptotic (e.g., Mcl1), heat shock (e.g., HSP40, HSP70, HSP90), and cell cycle promoting [e.g., cyclins B1, D1, and D3; cyclin-dependent kinase 1 (CDK1); MCM family proteins; proliferating cell nuclear antigen (PCNA)] proteins. BMS-690514-induced death of H1975 cells was modified in a unique fashion by a panel of small interfering RNAs targeting apoptosis modulators. Down-regulation of components of the nuclear factor-kappaB survival pathway (e.g., p65, Nemo/IKK gamma, TAB2) sensitized cells to BMS-690514, whereas knockdown of proapoptotic factors (e.g., Puma, Bax, Bak, caspase-2, etc.) and DNA damage-related proteins (e.g., ERCC1, hTERT) exerted cytoprotective effects. BMS-690514 is a new pan-HER/VEGFR inhibitor that may become an alternative to erlotinib for the treatment of NSCLC.
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PMID:A novel epidermal growth factor receptor inhibitor promotes apoptosis in non-small cell lung cancer cells resistant to erlotinib. 1761 83

Telomerase is a ribonucleoprotein complex that is essential for persistent cellular proliferation. The catalytic subunit of human telomerase, hTERT, functions as a reverse transcriptase and promotes vitality by maintaining telomeric DNA length. hTERT is tightly regulated with complex but poorly understood positive and negative regulation at several levels including transcription, protein-protein interactions, and post-translation modifications. Because evidence implicates hTERT as an apoptosis inhibitor and because telomerase activity tends to decrease during apoptosis, we hypothesized that hTERT is a caspase substrate leading to down regulation during apoptosis. Caspases are proteases that initiate and execute apoptosis by cleaving target proteins. Indeed, we found that caspases-6 and -7 cleave hTERT during apoptosis in cultured cells. Caspase-6 cleaves at residues D129 and D637, and caspase-7 cleaves at E286 and D628. Three of the caspase cleavage sites are unique motifs. All four caspase motifs appear conserved in TERTs from Old World monkeys and apes, and the caspase-6 sites appear conserved in all primates. The caspase site that cleaves at D129 appears conserved in amniotes. hTERT fragments generated by cleavage were remarkably persistent, lasting hours after caspase activation. These results reveal a new biologically relevant mechanism for telomerase down regulation through caspase-mediated cleavage of hTERT and expand the list of known caspase motifs.
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PMID:The catalytic subunit of human telomerase is a unique caspase-6 and caspase-7 substrate. 2193 63