Journal
CANCER LETTERS
Volume 357, Issue 1, Pages 307-315Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2014.11.041
Keywords
DNAJB1; PDCD5; p53; Ubiquitination; Apoptosis
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Funding
- National Research Foundation of Korea (NRF) grants - Korea Government (MSIP) [NRF-2012R1A2A1A01001862, NRF-2011-0030086]
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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 (Delta 180-210), 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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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