Destruction of DDIT3/CHOP protein by wild-type SPOP but not prostate cancer-associated mutants

Pingzhao Zhang, Kun Gao, Yan Tang, Xiaofeng Jin, Jian An, Hongxiu Yu, Huan Wang, Yuanyuan Zhang, Dejie Wang, Haojie Huang, Long Yu, Chenji Wang

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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. A. SPOP is one of the most frequently affected genes bysomatic point mutations in prostate cancer.

Original languageEnglish (US)
Pages (from-to)1142-1151
Number of pages10
JournalHuman mutation
Volume35
Issue number9
DOIs
StatePublished - Sep 2014

Keywords

  • DDIT3
  • Endoplasmic reticulum stress
  • Prostate cancer
  • Proteasomal degradation
  • SPOP

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Destruction of DDIT3/CHOP protein by wild-type SPOP but not prostate cancer-associated mutants'. Together they form a unique fingerprint.

  • Cite this

    Zhang, P., Gao, K., Tang, Y., Jin, X., An, J., Yu, H., Wang, H., Zhang, Y., Wang, D., Huang, H., Yu, L., & Wang, C. (2014). Destruction of DDIT3/CHOP protein by wild-type SPOP but not prostate cancer-associated mutants. Human mutation, 35(9), 1142-1151. https://doi.org/10.1002/humu.22614