4.5 Article

Destruction of DDIT3/CHOP Protein by Wild-Type SPOP but Not Prostate Cancer-Associated Mutants

期刊

HUMAN MUTATION
卷 35, 期 9, 页码 1142-1151

出版社

WILEY-BLACKWELL
DOI: 10.1002/humu.22614

关键词

DDIT3; SPOP; prostate cancer; proteasomal degradation; endoplasmic reticulum stress

资金

  1. National Key Sci-Tech Special Project of China [2008ZX10002-020]
  2. National Natural Science Foundation of China [30872947, 31071193, 81171964]

向作者/读者索取更多资源

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 CUL3-RBX1 E3 ubiquitin ligase complex and selectively recruits substrates for their ubiquitination and subsequent degradation. DDIT3 is an endoplasmic reticulum (ER) stress-responsive transcription factor playing an essential role in apoptotic execution pathways triggered by ER stress. Here, we identified DDIT3/CHOP as a bona fide substrate for the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. SPOP recognizes a Ser/Thr-rich degron in the transactivation domain of DDIT3 and triggers DDIT3 degradation via the ubiquitin-proteasome pathway. Strikingly, prostate cancer-associated mutants of SPOP are defective in promoting DDIT3 degradation. This study reveals novel molecular events underlying the regulation of DDIT3 protein homeostasis and provides insight in understanding the relationship between SPOP mutations and ER stress dysregulation in prostate cancer. (C) 2014 Wiley Periodicals, Inc.

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