tailieunhanh - Báo cáo khoa học: Regulation of DNp63a by tumor necrosis factor-a in epithelial homeostasis

A dominant negative form of p63,DNp63a, is critical for maintaining the proliferative potential of epidermal stem cells and progenitor cells. The expression ofDNp63aalso confers a selective advantage for cancer cell survival, underscoring the importance of DNp63a in both normal and neoplastic stratified epithelia. | ỊFEBS Journal Regulation of DNp63a by tumor necrosis factor-a in epithelial homeostasis Hae-ock Lee1 Jung-Hwa Lee1 Tae-You Kim2 and Hyunsook Lee1 1 Department of BiologicalSciences and Research Center for FunctionalCellulomics SeoulNationalUniversity Korea 2 Department of InternalMedicine Cancer Research Institute SeoulNationalUniversity College of Medicine Korea Keywords apoptosis ANp63a NF-kB TNF-a ubiquitindependent proteolysis Correspondence H. Lee Department of Biological Sciences and Research Center for Functional Cellulomics SeoulNationalUniversity San56-1 Shillim-dong Gwanak-ku Seoul 151-742 Korea Fax 82 2 886 4335 Tel 82 2 880 9121 E-mail HL212@ Received 18 July 2007 revised 1 October 2007 accepted 26 October 2007 doi A dominant negative form of p63 DNp63a is critical for maintaining the proliferative potential of epidermal stem cells and progenitor cells. The expression of DNp63a also confers a selective advantage for cancer cell survival underscoring the importance of DNp63a in both normal and neoplastic stratified epithelia. Regulation of DNp63a can be achieved at the transcriptional and post-translational levels the latter being greatly influenced by external stimuli such as UV irradiation. In this study we have found that tumor necrosis factor-a TNF-a a multifunctional cytokine that has been implicated in epidermal homeostasis during normal and pathophysiologic conditions also triggers the degradation of DNp63a in immortalized keratinocytes and cervical cancer cells. Conversely downregulation of DNp63a sensitized cancer cells to TNF-a-induced apoptosis suggesting a counteractive interaction between TNF-a and DNp63a in the regulation of epithelial cell death. The degradation of DNp63a by TNF-a was delayed when cells were treated with nuclear factor-kB inhibitors whereas the induction of apoptosis by TNF-a was accompanied by the dramatic upregulation of the proapoptotic gene Puma. These observations further .