Decreased survival of C/EBP beta-deficient keratinocytes is due to aberrant regulation of p53 levels and function.
Recent studies have identified roles for C/EBPbeta in cellular survival and tumorigenesis, however, the mechanisms through which C/EBPbeta regulates these processes are not fully understood. Previously, we demonstrated that C/EBPbeta(-/-) mice are resistant to carcinogen-induced skin tumorigenesis and in response to topical carcinogen treatment display a 17-fold increase in keratinocyte apoptosis compared to wild-type mice. Here, we have investigated the mechanisms through which C/EBPbeta regulates apoptosis in response to carcinogenic stress. Analysis of carcinogen-treated C/EBPbeta(-/-) mouse skin revealed a striking increase in the number of p53 immunopositive keratinocytes in the epidermis of C/EBPbeta(-/-) mice compared to wild-type mice and this increase was temporally associated with a concomitant anomalous increase in apoptosis. The increased levels of p53 were functional as Mdm2, Bcl-2, C/EBPalpha and p21 were differentially regulated in the epidermis of carcinogen-treated C/EBPbeta(-/-) mice. The increase in p53 protein was not associated with an increase in p53 mRNA levels. To determine whether p53 is required for the increased apoptosis in C/EBPbeta(-/-) mice, C/EBPbeta/p53 compound knockout mice were generated. Carcinogen-treated C/EBPbeta/p53 compound knockout mice did not display increased apoptosis demonstrating p53 is required for the proapoptotic phenotype in C/EBPbeta(-/-) mice. Our results demonstrate that altered keratinocyte survival in C/EBPbeta(-/-) mice results from aberrant regulation of p53 protein and function and indicate C/EBPbeta has a role in the negative regulation of p53 protein levels in response to carcinogen-induced stress.
Yoon
K
K
Cell Signaling and Cancer Group, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633, USA.
Zhu
S
S
Ewing
S J
SJ
Smart
R C
RC
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000502:physiology*; D002273:Carcinogens / Q000633:toxicity; D002470:Cell Survival; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D022782:CCAAT-Enhancer-Binding Protein-beta; D002273:Carcinogens; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D016283:Proto-Oncogene Proteins p21(ras)