title: The ubiquitin ligase CHIP regulates c-Myc stability and transcriptional activity.
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.
authors.affiliation: Laboratory of Signal transduction in cancer and Stem cells, Indian Institute of Chemical Biology IICB, Council of Scientific and Industrial Research CSIR, Kolkata, India.
authors.forename: I
authors.initials: I
authors.lastname: Paul
authors.forename: S F
authors.initials: SF
authors.lastname: Ahmed
authors.forename: A
authors.initials: A
authors.lastname: Bhowmik
authors.forename: S
authors.initials: S
authors.lastname: Deb
authors.forename: M K
authors.initials: MK
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex