P63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis (Cancer Cell, 2006, 9:45-56)

報告日期: 2006/04/14
報告時間: 17:10/18:00
報告學生: 黃佳韋
講評老師: 張敏政
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p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis

 

CANCER CELL 9, 45–56, JANUARY 2006

 

Speaker: 黃佳韋                      Date: 2006/04/14

Commentator: 張敏政 老師             Place: Room 602

 

 

Abstract

 

Several years ago, tumor suppressor genes p73 and p63 joined the ranks of the p53 family. Both of these new members give rise to various protein isotypes predicting complex transcriptional activity. Tumor progression usually involves blockage of normally regulated cell cycle control and apoptosis mediated by tumor suppressor genes at the cellular level. As we known, p53 mutations are very common in cancers; however, whether the altered levels and status of other p53 family are correlated with tumor progression remains unclear. Here the authors demonstrate that a dominant negative isotype of p63, ΔNp63α, is an essential survival factor in head and neck squamous cell carcinoma (HNSCC) through its ability to suppress p73-dependent apoptosis. Inhibition of endogenous p63 expression by RNAi induces apoptosis selectively in HNSCC cells that overexpress ΔNp63α. Knockdown of p63 induces the proapoptotic bcl-2 family members Puma and Noxa, and both their induction and subsequent cell death are p53 independent but require transactivating isoforms of p73. Inhibition of p73-dependent transcription by ΔNp63α involves both direct promoter binding and physical interaction with p73. In HNSCC cells lacking endogenous ΔNp63α expression, bcl-2 is instead upregulated and can suppress p73-mediated death. Together, these data define a pathway whereby ΔNp63α promotes survival in squamous epithelial malignancy by repressing a p73-dependent proapoptotic transcriptional program. Form the work presented here, it is becoming clear that in addition to the known role of p53, both p63 and p73 are critical mediators of cell death following chemotherapy in HNSCC.