Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA damage can lead to either DNA repair with cell survival or to apoptotic cell death. Although the biochemical processes underlying DNA repair and apoptosis have been extensively studied, the mechanisms by which cells determine whether the damage will be repaired or the apoptotic pathway will be activated is largely unknown. We have studied the role of nucleotide excision repair (NER) in cisplatin DNA damage-induced apoptotic cell death using both normal human fibroblasts and NER-defective xeroderma pigmentosum (XP) XPA and XPG cells. The caspase-3 activation experiment demonstrated a greatly increased casapse-3 activation in the NER-defective cells following cisplatin treatment. The flow cytometry experiment revealed an altered cell cycle arrest pattern of the NER-defective cells following cisplatin treatment. The results obtained from the Western blot experiment showed that NER defects resulted in enhanced CHK1 phosphorylation and p21 induction after cisplatin treatment. The cisplatin treatment-induced ATM phosphorylation, however, was attenuated in NER-defective cells. The results obtained from our immunoprecipitation experiment further demonstrated that the ATM protein interacted with the TFIIH basal transcription factor and the XPG protein of the NER pathway. It also showed that a functional XPC protein was required for the association of the ATM protein to genomic DNA. These results suggest that the NER process may prevent the cisplatin treatment-induced apoptosis by activating the ATM protein, and that the presence of the XPC protein is essential for recruiting the ATM protein to the DNA template.
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PMID:The involvement of ataxia-telangiectasia mutated protein activation in nucleotide excision repair-facilitated cell survival with cisplatin treatment. 1684 32

Mildly affected individuals from xeroderma pigmentosum complementation group G (XP-G) possess single amino acid substitutions in the XPG protein that adversely affects its 3' endonuclease function in nucleotide excision repair. More serious mutations in the XPG gene generate truncated or unstable XPG proteins and result in a particularly early and severe form of the combined XP/CS complex. Following UV irradiation, cells from such XP-G/CS patients enter apoptosis more readily than other DNA repair-deficient cells. Here, we explore the mechanisms by which UV triggers the apoptotic cell death program in XP-G and XP-G/CS primary fibroblasts. Activation of the CD95 signalling pathway occurs within minutes and it is the earliest detectable post-UV event in such cells. This is rapidly followed by activation of caspase-8 then caspase-3. Several hours later caspase-9 becomes activated and the mitochondrial membrane potential drops, but without any obvious prior release of cytochrome c. Although p53 accumulates in XPG-deficient cells after UV irradiation, use of RNA interference demonstrates that p53 is not required for their UV-induced apoptotic response. p53 ablation of wild-type fibroblasts reduces MDM2 mRNA levels, inhibits accumulation of the 90kDa/92kDa Mdm2 isoforms, and prevents the nuclear relocalisation of Mdm2 after UV treatment. The same post-UV effects occur in XPG-deficient cells that express normal p53 levels. These results emphasise the importance of the extrinsic apoptotic pathway and aberrant Mdm2 events for the severe UV-induced apoptosis of XPG-deficient primary fibroblasts. XP-G/CS cells constitutively overexpress the pro-apoptotic Bax protein and a long isoform of the E2F1 transcription factor that controls S phase entry, which may prime them to enter apoptosis very readily after UV irradiation.
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PMID:UV-induced apoptosis in XPG-deficient fibroblasts involves activation of CD95 and caspases but not p53. 1720 56