4.8 Article

Molecular Chaperone HSP90 Is Necessary to Prevent Cellular Senescence via Lysosomal Degradation of p14ARF

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CANCER RESEARCH
卷 77, 期 2, 页码 343-354

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-16-0613

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  1. Basic Science Research Program of the National Research Foundation of Korea (NRF) - Ministry of Science, ICT and Future Planning [2014R1A1A1002589]
  2. Creative Research Initiative Program of NRF - Ministry of Science, ICT and Future Planning [2015R1A3A2066581]
  3. National Cancer Center, Korea [NCC-1420300]
  4. National Research Foundation of Korea [2015R1A3A2066581, 2014R1A1A1002589] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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The tumor suppressor function of p14ARF is regulated at a posttranslational level via mechanisms yet to be fully understood. Here, we report the identification of an unconventional p14ARF degradation pathway induced by the chaperone HSP90 in association with the E3 ubiquitin ligase C-terminus of HSP70-interacting protein (CHIP). The ternary complex of HSP90, CHIP, and p14ARF was required to induce the lysosomal degradation of p14ARF by an ubiquitination-independent but LAMP2A-dependent mechanism. Depletion of HSP90 or CHIP induced p14ARF-dependent senescence in human fibroblasts. Premature senescence observed in cells genetically deficient in CHIP was rescued in cells that were doubly deficient in CHIP and p14ARF. Notably, non-small cell lung cancer cells (NSCLC) positive for p14ARF were sensitive to treatment with the HSP90 inhibitor geldanamycin. Furthermore, overexpression of HSP90 and CHIP with a concomitant loss of p14ARF correlated with poor prognosis in patients with NSCLC. Our findings identify a relationship between p14ARF and its chaperones that suggest new therapeutic strategies in cancers that overexpress HSP90. (C) 2016 AACR.

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