DNAJB1 destabilizes PDCD5 to suppress p53-mediated apoptosis. Issue 1 (1st February 2015)

• Record Type: Journal Article
• Authors: Cui, Xiandan; Choi, Hyo-Kyoung; Choi, Young-Seok; Park, Soo-Yeon; Sung, Gi-Jun; Lee, Yoo-Hyun; Lee, Jeongmin; Jun, Woo Jin; Kim, Kyungsup; Choi, Kyung-Chul; Yoon, Ho-Geun
• Is Part Of: Cancer letters. Volume 357:Issue 1(2015)
• Page Start: 307
• Page End: 315
• Publication Date: 2015-02-01
• Subjects: DNAJB1 -- PDCD5 -- p53 -- Ubiquitination -- Apoptosis; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2014.11.041
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: DNAJB1 binds to and reduces stability via ubiquitin-dependent PDCD5 degradation. PDCD5 was localized by DNAJB1 in the cytoplasm. DNAJB1 negatively regulates PDCD5 to inhibit p53 activation and knockdown of DNAJB1 increases genotoxic stress. Depletion of PDCD5 abrogates the effect of DNAJB1 knockdown on p53 activation. Abstract: Although PDCD5 promotes p53-mediated apoptosis in various cancers, little is known about PDCD5 regulation. We recently found that DNAJB1 interacts with PDCD5 and induces the ubiquitin-dependent proteasomal degradation of PDCD5, thereby inhibiting p53-mediated apoptosis. To investigate these novel roles for PDCD5 and DNAJB1, we performed DNAJB1 mapping with PDCD5. PDCD5 specifically binds to the DNAJB1-D5 domain (Δ180–210), which was found to be essential for the stabilization of PDCD5. Further study showed that DNAJB1 post-translationally regulates PDCD5 stability. DNAJB1 ubiquitinated PDCD5 via a ubiquitin-mediated pathway. In human lung A549 cancer cells, DNAJB1 promoted the ubiquitination and degradation of PDCD5 and inhibited p53 activation. However, DNAJB1 knockdown in A549 cells increased the etoposide-induced activation of the p53-mediated apoptosis pathway and repressed cancer cell growth. Because this function was p53 dependent, DNAJB1 depletion increased the expression of p53-targeted apoptosis genes. In conclusion, we screened a novel PDCD5-associating protein, DNAJB1, by yeast two-hybrid screening and provided evidences that DNAJB1 targets PDCD5 to suppress p53-dependent apoptosis of cancer cells. Thus, we identified DNAJB1 as a negative regulator of PDCD5-mediated apoptosis and found that the apoptosis network of PDCD5 regulates cancer cell death.