p53 regulates cellular resistance to complement lysis through enhanced expression of CD59.
It has been recently hypothesized that the CD59 gene has two putative p53-responsive elements that may be involved in defense of host cells from damage by the complement system in inflammation. Here we have examined the roles of these putative p53-binding sequences within the CD59 gene in regulation of CD59 expression. We have shown that both of these potential responsive elements bind p53 in vitro. Knocking down expression of p53 using small interfering RNA led to a 6-fold decrease in CD59 protein expression in HeLa cells. We have previously observed a decrease of CD59 in camptothecin-induced apoptotic IMR32 cells, whereas expression was increased in the surviving fraction compared with untreated cells. Here, we have shown that these changes are associated with altered expression levels and acetylation status of p53. We have also shown that acetylation status of p53 regulates CD59 expression on cells exposed to inflammatory cytokines to model inflammation. Our data suggest that p53 and in vivo positive/negative regulators of p53 could be used to modulate susceptibility of tumor cells to complement lysis in chemotherapy.
Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Rossen M
RM
Donev
Duncan S
DS
Cole
Baalasubramanian
B
Sivasankar
Timothy R
TR
Hughes
B Paul
BP
Morgan
D000107:Acetylation; D018957:CD59 Antigens / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D002166:Camptothecin / Q000494:pharmacology; D003165:Complement System Proteins / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007438:Introns; D011401:Promoter Regions, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism
D018957:CD59 Antigens; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003165:Complement System Proteins; D002166:Camptothecin