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

Paul, Indranil; Ahmed, Syed Feroj; Bhowmik, Arijit; Deb, Satamita; Ghosh, Mrinal K.

doi:10.1038/onc.2012.144

Cited by 140 publications

(115 citation statements)

References 43 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…Some ubiquitin ligases (CHIP) link chaperones and the 26S proteasome machinery by ubiquitinating chaperone substrates and channeling them toward the proteasome (76)(77)(78). Chaperones are among the proteins increased to the highest levels (ϳ16.7-to 27-fold) in the MAM of HCMV-infected cells (37).…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Inhibits Apoptosis by Proteasome-Mediated Degradation of Bax at Endoplasmic Reticulum-Mitochondrion Contacts

Zhang

Hildreth

Colberg-Poley

2013

J Virol

View full text Add to dashboard Cite

Human cytomegalovirus (HCMV) encodes the UL37 exon 1 protein (pUL37x1), which is the potent viral mitochondrion-localized inhibitor of apoptosis (vMIA), to increase survival of infected cells. HCMV vMIA traffics from the endoplasmic reticulum (ER) to ER subdomains, which are physically linked to mitochondria known as mitochondrion-associated membranes (MAM), and to mitochondria. The antiapoptotic function of vMIA is thought to primarily result from its ability to inhibit Bax-mediated permeabilization of the outer mitochondrial membrane (OMM). Here, we establish that vMIA retargets Bax to the MAM as well as to the OMM from immediate early through late times of infection. However, MAM localization of Bax results in its increased ubiquitination and proteasome-mediated degradation. Surprisingly, HCMV infection does not increase OMM-associated degradation (OMMAD) of Bax, even though the ER and mitochondria are physically connected at the MAM. It was recently found that lipid rafts at the plasma membrane can connect extrinsic and intrinsic apoptotic pathways and can serve as sites of apoptosome assembly. In transfected permissive human fibroblasts, vMIA mediates, through its cholesterol affinity, association of Bax and apoptosome components with MAM lipid rafts. While Bax association with MAM lipid rafts was detected in HCMV-infected cells, association of apoptosome components was not. These results establish that Bax recruitment to the MAM and its MAMassociated degradation (MAMAD) are a newly described antiapoptotic mechanism used by HCMV infection to increase cell survival for its growth.

show abstract

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Inhibits Apoptosis by Proteasome-Mediated Degradation of Bax at Endoplasmic Reticulum-Mitochondrion Contacts

Zhang

Hildreth

Colberg-Poley

2013

J Virol

View full text Add to dashboard Cite

show abstract

“…The most recent ubiquitin ligase to be identified for MYC is CHIP (carboxyl terminus of Hsc70-interacting protein) (Paul et al 2013). CHIP is a chaperone-associated U-box-containing E3 ligase that links a chaperone to the 26S proteasome machinery by ubiquitinating chaperone substrates and directing them toward the proteasome (Ballinger et al 1999).…”

Section: Chipmentioning

confidence: 99%

MYC Degradation

Farrell

Sears²

2014

Cold Spring Harbor Perspectives in Medicine

378

333

View full text Add to dashboard Cite

The MYC oncoprotein is an essential transcription factor that regulates the expression of many genes involved in cell growth, proliferation, and metabolic pathways. Thus, it is important to keep MYC activity in check in normal cells in order to avoid unwanted oncogenic changes. Normal cells have adapted several ways to control MYC levels, and these mechanisms can be disrupted in cancer cells. One of the major ways in which MYC levels are controlled in cells is through targeted degradation by the ubiquitin-proteasome system (UPS). Here, we discuss the role of the UPS in the regulation of MYC protein levels and review some of the many proteins that have been shown to regulate MYC protein stability. In addition, we discuss how this relates to MYC transcriptional activity, human cancers, and therapeutic targeting.

show abstract

“…20 Several E3 ligases, including FBW7, SKP2, TRUSS, HectH9, β-Trcp1 and Hsc70-interacting protein (CHIP), have been identified as responsible for c-Myc degradation. 19,[22][23][24][25][26][27][28] However, it is still unclear whether c-Myc stability is regulated by ubiquitin-independent pathways. In the present study, we demonstrated that proteasome activator REGγ is a novel negative regulator of c-Myc and provided evidence that this regulation is evolutionarily conserved.…”

mentioning

confidence: 99%

Regulation of c-Myc protein stability by proteasome activator REGγ

Jiang

Pan

et al. 2014

Cell Death Differ

View full text Add to dashboard Cite

-Myc is a key transcriptional factor that has a prominent role in cell growth, differentiation and tumor development. Its protein levels are tightly controlled by ubiquitin-proteasome pathway and frequently deregulated in various cancers. Here, we report that the 11S proteasomal activator REGγ is a novel regulator of c-Myc abundance in cells. We showed that overexpression of wild-type REGγ, but not inactive mutants including N151Y and G250S, significantly promoted the degradation of c-Myc. Depletion of REGγ markedly increased the protein stability of c-Myc. REGγ interacts with the C-terminal region of c-Myc and regulates c-Myc protein turnover. Functionally, REGγ negatively regulates c-Myc-mediated cell proliferation. Interestingly, depletion of the Drosophila Reg homolog (dReg) in developing wings induced the upregulation of Drosophila Myc, which contributes to cell death. Collectively, these results suggest that REGγ proteasome has a conserved role in the regulation of Myc abundance in both mammalian cells and Drosophila.

show abstract

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

Cited by 140 publications

References 43 publications

Human Cytomegalovirus Inhibits Apoptosis by Proteasome-Mediated Degradation of Bax at Endoplasmic Reticulum-Mitochondrion Contacts

Human Cytomegalovirus Inhibits Apoptosis by Proteasome-Mediated Degradation of Bax at Endoplasmic Reticulum-Mitochondrion Contacts

MYC Degradation

Regulation of c-Myc protein stability by proteasome activator REGγ

Contact Info

Product

Resources

About