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Decreased survival of C/EBPβ-deficient keratinocytes is due to aberrant regulation of p53 levels and function

Oncogene volume 26, pages 360–367 (2007)Cite this article

Abstract

Recent studies have identified roles for C/EBPβ in cellular survival and tumorigenesis, however, the mechanisms through which C/EBPβ regulates these processes are not fully understood. Previously, we demonstrated that C/EBPβ−/− 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/EBPβ regulates apoptosis in response to carcinogenic stress. Analysis of carcinogen-treated C/EBPβ−/− mouse skin revealed a striking increase in the number of p53 immunopositive keratinocytes in the epidermis of C/EBPβ−/− 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/EBPα and p21 were differentially regulated in the epidermis of carcinogen-treated C/EBPβ−/− 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/EBPβ−/− mice, C/EBPβ/p53 compound knockout mice were generated. Carcinogen-treated C/EBPβ/p53 compound knockout mice did not display increased apoptosis demonstrating p53 is required for the proapoptotic phenotype in C/EBPβ−/− mice. Our results demonstrate that altered keratinocyte survival in C/EBPβ−/− mice results from aberrant regulation of p53 protein and function and indicate C/EBPβ has a role in the negative regulation of p53 protein levels in response to carcinogen-induced stress.

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Acknowledgements

We would like to thank Dr Cavell Brownie for help with the statistical analysis. This work was supported by a grant CA46637 from the National Cancer Institute.

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  1. K Yoon

    Present address: Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA

  2. K Yoon and S Zhu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Environmental and Molecular Toxicology, Cell Signaling and Cancer Group, North Carolina State University, Raleigh, NC, USA

    K Yoon, S Zhu, S J Ewing & R C Smart

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  1. K Yoon
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Correspondence to R C Smart.

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Yoon, K., Zhu, S., Ewing, S. et al. Decreased survival of C/EBPβ-deficient keratinocytes is due to aberrant regulation of p53 levels and function. Oncogene 26, 360–367 (2007). https://doi.org/10.1038/sj.onc.1209797

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