Restoration of p53 expression in human cancer cell lines upregulates the expression of Notch1: implications for cancer cell fate determination after genotoxic stress.
Following genotoxic stress, transcriptional activation of target genes by p53 tumor suppressor is critical in cell fate determination. Here we report that the restoration of p53 function in human cancer cell lines that are deficient in p53 function upregulated the expression of Notch1. Interestingly, the expression of wild-type p53 in human prostate and breast cancer cell lines correlated well with increased expression of Notch1. Furthermore, knockdown of p53 expression in cancer cells that express wild-type p53 resulted in reduced expression of Notch1. Importantly, genotoxic stress to cancer cells that resulted in activation of p53 also upregulated the expression of Notch1. Moreover, p53-mediated induction of Notch1 expression was associated with stimulation of the activity of Notch-responsive reporters. Notably, p53 differentially regulated the expression of Notch family members: expression of Notch2 and Notch4 was not induced by p53. Significantly, treatment of cells with gamma secretase inhibitor, an inhibitor of Notch signaling, increased susceptibility to apoptosis in response to genotoxic stress. Together, our observations suggest that p53-mediated upregulation of Notch1 expression in human cancer cell lines contributes to cell fate determination after genotoxic stress.
Alimirah
Fatouma
F
Edward Hines Jr. VA Hospital, 5th Avenue and Roosevelt Road, Building 1, Mail Code 114B, Hines, IL 60141, USA.
Panchanathan
Ravichandran
R
Davis
Francesca J
FJ
Chen
Jianming
J
Choubey
Divaker
D
D017209:Apoptosis; D045744:Cell Line, Tumor; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D051881:Receptor, Notch1 / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D015854:Up-Regulation
C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; D005047:Etoposide