Proteolytic Control of the Oncoprotein Transcription Factor Myc

Thomas, Lance R.; Tansey, William P.

doi:10.1016/b978-0-12-386469-7.00004-9

Cited by 101 publications

(111 citation statements)

References 123 publications

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“…20 In this study, we identified a novel ubiquitination-independent pathway regulating the protein levels of c-Myc. We found that the proteasome activator REGγ controls the abundance of c-Myc proteins by regulating protein stability.…”

Section: Discussionmentioning

confidence: 91%

“…18 c-Myc is a highly unstable protein and is usually degraded in o30 min in cells. 19,20 Deregulated reduction of c-Myc protein degradation results in the accumulation of c-Myc in many cancers that may contribute to uncontrolled cell proliferation. 21 However, most reported pathways that control c-Myc protein degradation are ubiquitindependent proteasome pathways.…”

mentioning

confidence: 99%

“…21 However, most reported pathways that control c-Myc protein degradation are ubiquitindependent proteasome pathways. 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.…”

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confidence: 99%

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Regulation of c-Myc protein stability by proteasome activator REGγ

Jiang

Pan

et al. 2014

Cell Death Differ

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-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.

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Section: Discussionmentioning

confidence: 91%

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confidence: 99%

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confidence: 99%

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Regulation of c-Myc protein stability by proteasome activator REGγ

Jiang

Pan

et al. 2014

Cell Death Differ

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“…153 Some reports suggest that MAPK inhibition may induce a synthetic lethal interaction with MYC. Indeed, the first example of oncogenic cooperation reported was that of MYC and RAS in the transformation of primary mouse fibroblasts.…”

Section: Mapk Inhibitorsmentioning

confidence: 99%

MYC as therapeutic target in leukemia and lymphoma

Cortiguera¹,

Batlle-López²,

Albajar³

et al. 2015

BLCTT

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MYC is a transcription factor that is involved in the expression of many genes. Deregulated MYC is found in about half of human tumors, being more prevalent in hematological neoplasms. Deregulation mechanisms include chromosomal translocation (particularly in lymphoma), amplification, and hyperactivation of MYC transcription. Here we review MYC involvement in the major types of leukemia and lymphoma. MYC rearrangements appear in all Burkitt lymphomas and are common in other lymphoma types, whereas in acute lymphoblastic leukemia, acute myeloid leukemia, lymphoproliferative, and myeloproferative diseases, they are less frequent. However, MYC overexpression is present in all types of hematological malignancies and often correlates with a worse prognosis. Data in leukemia-derived cells and in animal models of lymphomagenesis and leukemogenesis suggest that MYC would be a good therapeutic target. Several MYC-directed therapies have been assayed in preclinical settings and even in clinical trials. First, peptides and small molecules that interrupt the MYC-MAX interaction impair MYCmediated tumorogenesis in several mouse models of solid tumors, although not yet in lymphoma and leukemia models. Second, there are a number of small molecules inhibiting the interaction of MYC-MAX heterodimers with DNA, still in the preclinical research phase. Third, inhibitors of MYC expression via the inhibition of BRD4 (a reader of acetylated histones) have been shown to control the growth of MYC-transformed leukemia and lymphoma cells and are being used in clinic trials. Finally, we review a number of promising MYC-mediated synthetic lethal approaches that are under study and have been tested in hematopoietic neoplasms.

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“…c-Myc levels can be subject to several modes of regulation, going from posttranslational control to mRNA stability and transcriptional regulation [41][42][43][44]. The c-myc gene, although it contains a dual promoter, is predominantly transcribed from the P2 promoter [45].…”

Section: Id2 During G0-g1 Transitionmentioning

confidence: 99%