hMSH2 expression is driven by AP1-dependent regulation through phorbol-ester exposure.
Mammalian mismatch repair (MMR) plays a prominent role in genomic stability and toxicity induced by some DNA damaging agents. Advance in the appreciation of regulation mechanisms of the key MMR protein hMSH2 would certainly lead to valuable information on its role and to a better understanding of MMR system dysfunctions with respect to their consequences in cells. We have previously reported that, in myeloid leukemic U937 cell line, the expression of hMSH2 MMR protein is regulated by protein kinase C (PKC) activity. Here we show that the increase of protein level following PKC activation by phorbol ester (TPA) treatment parallels that of hMSH2 mRNA. Our results support the view that the hMSH2 gene is prone to transcriptional regulation upon TPA induction, and that AP-1 is a factor implicated in the transactivation. When losing the AP-1-dependent hMSH2 promoter activity, either by mutating the AP-1 binding sites of the hMSH2 promoter or by using a dominant negative c-Jun factor, the hMSH2 overexpression induced by TPA is abolished both in vitro and in vivo. Thus the control of hMSH2 expression by PKC appears to be dependent, at least partially, on an up-regulation mediated by AP-1 transactivation.
D001483:Base Sequence; D001665:Binding Sites; D004268:DNA-Binding Proteins; D006367:HeLa Cells; D006801:Humans; D051718:MutS Homolog 2 Protein; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D020218:Response Elements; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D020298:U937 Cells
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D011493:Protein Kinase C; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein; D013755:Tetradecanoylphorbol Acetate