A dominant negative form of p63 inhibits apoptosis in a p53-independent manner.
Stem cells are a source of differentiated cells in multiple tissues. If genetic alterations occur in stem cells, the problem persists and malignant cancers may arise. DeltaNp63alpha-a homologue of the tumor suppressor p53-is exclusively expressed in proliferating undifferentiated epithelial cells and cancer cells of epidermal origin. Here, we show that DeltaNp63alpha antagonizes DNA damage-induced apoptosis in a p53-independent manner. We found that upon cellular injury, DeltaNp63alpha must be downregulated before apoptotic program can be activated. The 5637 cell line has abundant levels of DeltaNp63alpha and mutant p53, and it is resistant to DNA damage-induced apoptosis. The knockdown of DeltaNp63alpha by RNA interference sensitized these cells to apoptosis upon genotoxic insult. This suggests that DeltaNp63alpha plays an anti-apoptotic role regardless of the p53 status. Considering the frequent mutations of p53 in tumor cells, our results provide important implications for the treatment of cancers in which p63 is amplified.
Lee
Hae-ock
HO
Department of Biological Sciences, Research Center for Functional Cellulomics, College of Natural Sciences, Seoul National University, San 56-1 Shillim-dong, Gwanak-ku, Seoul 151-742, Republic of Korea.
Lee
Jung-Hwa
JH
Choi
Eunhee
E
Seol
Ja Young
JY
Yun
Yungdae
Y
Lee
Hyunsook
H
D017209:Apoptosis / Q000235:genetics*; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D006801:Humans; D009154:Mutation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins