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Regulation of c-Myc protein stability by proteasome activator REG?.

ABSTRACT: c-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 REG? is a novel regulator of c-Myc abundance in cells. We showed that overexpression of wild-type REG?, but not inactive mutants including N151Y and G250S, significantly promoted the degradation of c-Myc. Depletion of REG? markedly increased the protein stability of c-Myc. REG? interacts with the C-terminal region of c-Myc and regulates c-Myc protein turnover. Functionally, REG? 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 REG? proteasome has a conserved role in the regulation of Myc abundance in both mammalian cells and Drosophila.

SUBMITTER: Li S

PROVIDER: S-EPMC4423183 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Regulation of c-Myc protein stability by proteasome activator REGγ.

Li S S Jiang C C Pan J J Wang X X Jin J J Zhao L L Pan W W Liao G G Cai X X Li X X Xiao J J Jiang J J Wang P P

Cell death and differentiation 20141121 6

c-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. Depl ...[more]

PMID: 25412630

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Project description:There are two immune responses in vertebrates: humoral immunity is mediated by circulating antibodies, whereas cytotoxic T lymphocytes (CTL) confer cellular immunity. CTL lyse infected cells upon recognition of cell-surface MHC Class I molecules complexed with foreign peptides. The displayed peptides are produced in the cytosol by degradation of host proteins or proteins from intracellular pathogens that might be present. Proteasomes are cylindrical multisubunit proteases that generate many of the peptides eventually transferred to the cell surface for immune surveillance. In mammalian proteasomes, six active sites face a central chamber. As this chamber is sealed off from the enzyme's surface, there must be mechanisms to promote entry of substrates. Two protein complexes have been found to bind the ends of the proteasome and activate it. One of the activators is the 19 S regulatory complex of the 26 S proteasome; the other activator is '11 S REG' [Dubiel, Pratt, Ferrell and Rechsteiner (1992) J. Biol. Chem. 267, 22369-22377] or 'PA28' [Ma, Slaughter and DeMartino (1992) J. Biol. Chem. 267, 10515-10523]. During the past 7 years, our understanding of the structure of REG molecules has increased significantly, but much less is known about their biological functions. There are three REG subunits, namely alpha, beta and gamma. Recombinant REGalpha forms a ring-shaped heptamer of known crystal structure. 11 S REG is a heteroheptamer of alpha and beta subunits. REGgamma is also presumably a heptameric ring, and it is found in the nuclei of the nematode work Caenorhabditis elegans and higher organisms, where it may couple proteasomes to other nuclear components. REGalpha and REGbeta, which are abundant in vertebrate immune tissues, are located mostly in the cytoplasm. Synthesis of REG alpha and beta subunits is induced by interferon-gamma, and this has led to the prevalent hypothesis that REG alpha/beta hetero-oligomers play an important role in Class I antigen presentation. In the present review we focus on the structural properties of REG molecules and on the evidence that REGalpha/beta functions in the Class I immune response.

Dataset Information

Regulation of c-Myc protein stability by proteasome activator REG?.

Publications

Regulation of c-Myc protein stability by proteasome activator REGγ.

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