U-box-type ubiquitin E4 ligase, UFD2a attenuates cisplatin mediated degradation of DeltaNp63alpha.
DeltaNp63alpha, the dominant negative isoform of the p63 family is an essential survival factor in head and neck squamous cell carcinoma. This isoform has been shown to be down regulated in response to several DNA damaging agents, including cisplatin. But little is understood about the post-translational protein stability of DeltaNp63alpha. In this present study we demonstrate for the first time that DeltaNp63alpha physically interacts with U-box-type E4 ubiquitin ligase UFD2a. UFD2a stabilizes DeltaNp63alpha, and ubiquitylation of DeltaNp63alpha is attenuated by UFD2a both in the presence and absence of cisplatin. Ectopic expression of UFD2a increased the half-life of DeltaNp63alpha in association with a significant enhancement of the repressive transcriptional activity of DeltaNp63alpha. Downregulation of endogenous UFD2a by RNAi resulted in degradation of DeltaNp63alpha. Taken together, our current study provides an insight onto the regulation of DeltaNp63alpha protein levels in response to cisplatin and also suggests that UFD2a might play an important role in the regulation of cisplatin mediated cell death mediated by p63.
Chatterjee
Aditi
A
Department of Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Research Division, The Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
Upadhyay
Sunil
S
Chang
Xiaofei
X
Nagpal
Jatin K
JK
Trink
Barry
B
Sidransky
David
D
D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics; D034622:RNA Interference / Q000502:physiology; D050436:Regulatory Elements, Transcriptional / Q000187:drug effects / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents; D012097:Repressor Proteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D043743:Ubiquitin-Protein Ligase Complexes; C473697:UBE4B protein, human; D044767:Ubiquitin-Protein Ligases; D002945:Cisplatin