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Destruction of DDIT 3/ CHOP Protein by Wild‐Type SPOP but Not Prostate Cancer‐Associated Mutants
Author(s) -
Zhang Pingzhao,
Gao Kun,
Tang Yan,
Jin Xiaofeng,
An Jian,
Yu Hongxiu,
Wang Huan,
Zhang Yuanyuan,
Wang Dejie,
Huang Haojie,
Yu Long,
Wang Chenji
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22614
Subject(s) - biology , ubiquitin ligase , unfolded protein response , endoplasmic reticulum associated protein degradation , prostate cancer , cancer research , ubiquitin , genetics , cancer , endoplasmic reticulum , gene
Characterization of the exome and genome of prostate cancers by next‐generation sequencing has identified numerous genetic alternations. SPOP (speckle‐type POZ protein) was identified as one of the most frequently affected genes by somatic point mutations in prostate cancer, suggesting SPOP is potentially a key driver for prostate cancer development and progression. However, how SPOP mutations contribute to prostate cancer remains to be elucidated. SPOP acts as an adaptor protein of the CUL 3– RBX 1 E 3 ubiquitin ligase complex and selectively recruits substrates for their ubiquitination and subsequent degradation. DDIT 3 is an endoplasmic reticulum ( ER ) stress‐responsive transcription factor playing an essential role in apoptotic execution pathways triggered by ER stress. Here, we identified DDIT 3/ CHOP as a bona fide substrate for the SPOP – CUL 3– RBX 1 E 3 ubiquitin ligase complex. SPOP recognizes a S er/ T hr‐rich degron in the transactivation domain of DDIT 3 and triggers DDIT 3 degradation via the ubiquitin–proteasome pathway. Strikingly, prostate cancer‐associated mutants of SPOP are defective in promoting DDIT 3 degradation. This study reveals novel molecular events underlying the regulation of DDIT 3 protein homeostasis and provides insight in understanding the relationship between SPOP mutations and ER stress dysregulation in prostate cancer.