Multifaceted C-terminus of HSP70-interacting protein regulates tumorigenesis via protein quality control
- 149 Downloads
C-terminus of heat shock protein 70 (HSP70)-interacting protein (CHIP) is an E3 ligase involved in a variety of protein homeostasis events implicated in diverse signaling pathways. Its involvement in varied and even opposite signaling circuits might be due to its hallmark signature of associating with molecular chaperones, including HSP90 and HSP70. Together, these proteins may be pivotal in implementing protein quality control. A curious and puzzling aspect of the function of CHIP is its capability to induce protein degradation via the proteasome- or lysosome-dependent pathways. In addition, these pathways are combined with ubiquitin-dependent or -independent pathways. This review focuses on the role of CHIP in the development or suppression of tumorigenesis. CHIP can act as a tumor suppressor by downregulating various oncogenes. CHIP also displays an oncogenic feature involving the inhibition of diverse tumor suppressors, including proteins related to intrinsic and extrinsic apoptotic pathways. The ability of CHIP to exhibit dual roles in determining the fate of cells has not been studied analytically. However, its association with various proteins involved in protein quality control might play a major role. In this review, the mechanistic roles of CHIP in tumor formation based on the regulation of diverse proteins are discussed.
KeywordsCHIP Chaperone Tumorigenesis Ubiquitination Cancer
This work was supported by grants from Creative Research Initiative Program of NRF (2015R1A3A2066581) funded by the Ministry of Science, ICT.
Compliance with ethical standards
Conflict of interest
The authors have declared that no conflict of interest exists.
- Ballinger CA, Connell P, Wu Y, Hu Z, Thompson LJ, Yin LY, Patterson C (1999) Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol 19:4535–4545PubMedPubMedCentralCrossRefGoogle Scholar
- Chung C, Yoo G, Kim T, Lee D, Lee CS, Cha HR, Park YH, Moon JY, Jung SS, Kim JO, Lee JC, Kim SY, Park HS, Park M, Park DI, Lim DS, Jang KW, Lee JE (2016) The E3 ubiquitin ligase CHIP selectively regulates mutant epidermal growth factor receptor by ubiquitination and degradation. Biochem Biophys Res Commun 479:152–158PubMedCrossRefPubMedCentralGoogle Scholar
- Gaude H, Aznar N, Delay A, Bres A, Buchet-Poyau K, Caillat C, Vigouroux A, Rogon C, Woods A, Vanacker JM, Hohfeld J, Perret C, Meyer P, Billaud M, Forcet C (2012) Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1. Oncogene 31:1582–1591PubMedCrossRefPubMedCentralGoogle Scholar
- Holland SJ, Pan A, Franci C, Hu Y, Chang B, Li W, Duan M, Torneros A, Yu J, Heckrodt TJ, Zhang J, Ding P, Apatira A, Chua J, Brandt R, Pine P, Goff D, Singh R, Payan DG, Hitoshi Y (2010) R428, a selective small molecule inhibitor of AXL kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res 70:1544–1554PubMedCrossRefPubMedCentralGoogle Scholar
- Kamalati T, Jolin HE, Mitchell PJ, Barker KT, Jackson LE, Dean CJ, Page MJ, Gusterson BA, Crompton MR (1996) Brk, a breast tumor-derived non-receptor protein-tyrosine kinase, sensitizes mammary epithelial cells to epidermal growth factor. J Biol Chem 271:30956–30963PubMedCrossRefPubMedCentralGoogle Scholar
- Maruyama T, Kadowaki H, Okamoto N, Nagai A, Naguro I, Matsuzawa A, Shibuya H, Tanaka K, Murata S, Takeda K, Nishitoh H, Ichijo H (2010) CHIP-dependent termination of MEKK2 regulates temporal ERK activation required for proper hyperosmotic response. EMBO J 29:2501–2514PubMedPubMedCentralCrossRefGoogle Scholar
- Naito AT, Okada S, Minamino T, Iwanaga K, Liu ML, Sumida T, Nomura S, Sahara N, Mizoroki T, Takashima A, Akazawa H, Nagai T, Shiojima I, Komuro I (2010) Promotion of CHIP-mediated p53 degradation protects the heart from ischemic injury. Circ Res 106:1692–1702PubMedCrossRefPubMedCentralGoogle Scholar
- Ozaki T, Nakagawara A, Nagase H (2013) RUNX family participates in the regulation of p53-dependent DNA damage response. Int J Genom 2013:271347Google Scholar