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The ubiquitin ligase CHIP regulates c-Myc stability and transcriptional activity

Oncogene volume 32, pages 1284–1295 (2013)Cite this article

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Abstract

c-Myc is a proto-oncogenic transcription factor and its rapid turnover mediated by the ubiquitin–proteasome system is critical for maintaining normal cellular homeostasis. Multiple ubiquitin ligases have been assigned for c-Myc regulation till date. However, the available data suggest for the possible existence of additional E3 ligase(s). Here, we report a new E3 ligase for c-Myc, the carboxyl terminus of Hsc70-interacting protein or CHIP, which is a chaperone-associated Ubox-containing E3 ligase. In this report, we show that CHIP interacts and ubiquitinates c-Myc, thus targeting it for proteasome-mediated degradation. Overexpression of CHIP could accelerate the turnover rate of c-Myc protein. Conversely, knockdown of CHIP by RNAi stabilizes endogenous c-Myc. The interaction between CHIP and c-Myc depends on the N-terminally located tetratricopeptide repeats of CHIP, which has been implicated as a chaperone-binding motif. Inhibition of Hsp90 chaperone activity by 17-N-allylamino-17-demethoxygeldanamycin reduces c-Myc protein level. We found that the association between CHIP and c-Myc is dependent on the chaperones; particularly Hsp70. CHIP antagonizes the transcriptional activity of c-Myc and decreases the abundance of the transcripts of its target genes. Overall, CHIP-knockdown increases malignant behavior of C6 glioma cells. To the best of our knowledge, this is the first report of c-Myc being regulated by a bona-fide chaperone-associated E3 ligase in HEK293 as well as glioma cells. Because CHIP has been reported earlier to be negatively regulating Akt1, BCR-ABL and hTERT, and now c-Myc, the present study may strengthen the view that CHIP acts as a tumor suppressor.

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Abbreviations

CHIP:

carboxyl terminus of Hsc70-interacting protein

H&E:

haematoxylin and eosin

17-AAG:

17-N-allylamino-17-demethoxygeldanamycin

Ni-NTA:

nickel-nitrilotriacetic acid

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Acknowledgements

This work was supported by grants provided by Council of Scientific and Industrial Research, CSIR (EMPOWER) and DST to MKG.

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  1. Laboratory of Signal transduction in cancer and Stem cells, Indian Institute of Chemical Biology (IICB), Council of Scientific and Industrial Research (CSIR), Kolkata, India

    I Paul, S F Ahmed, A Bhowmik, S Deb & M K Ghosh

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Correspondence to M K Ghosh.

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Paul, I., Ahmed, S., Bhowmik, A. et al. The ubiquitin ligase CHIP regulates c-Myc stability and transcriptional activity. Oncogene 32, 1284–1295 (2013). https://doi.org/10.1038/onc.2012.144

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