Che-1: a new effector of checkpoints signaling.
Che-1 is a RNA polymerase II binding protein involved in the transcriptional regulation of E2F target-genes and in cell proliferation. Recently, it has been shown that Che-1 accumulates in cells responding to genotoxic agents, such as Doxorubicin and ionizing radiations. The DNA damage-activated checkpoint kinases ATM and Chk2 interact with and phosphorylate Che-1, enhancing its accumulation and stability, and promoting Che-1-mediated transcription of p53-responsive genes and of p53 itself, as evidenced by microarray analysis. This transcriptional response is suppressed by expression of a Che-1 mutant lacking ATM and Chk2 phosphorylation amino acid residues, or by depletion of Che-1 by RNA silencing. In addition, chromatin immunoprecipitation analysis has shown that Che-1 is released from the E2F-target genes and recruited to the p21 and p53 promoters after DNA damage. Lastly, Che-1 contributes to the maintenance of the G2/M checkpoint in response to genotoxic stresses. These findings identify a new mechanism by which the checkpoint kinases regulate, via the novel effector Che-1, the p53 pathway.
Floridi
Aristide
A
Department of Experimental Medicine, Via Vetoio Coppito 2, University of L'Aquila, L'Aquila, Italy.
Fanciulli
Maurizio
M
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D050684:E2F Transcription Factors / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018816:Genes, cdc / Q000502:physiology*; D006801:Humans; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C402637:AATF protein, human; D051017:Apoptosis Regulatory Proteins; D050684:E2F Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53