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Post-translational regulation of Myc oncoprotein function

Bahram, Fuad (2004). Post-translational regulation of Myc oncoprotein function. Diss. (sammanfattning/summary) SLU : Sveriges lantbruksuniv., Acta Universitatis agriculturae Sueciae. Agraria, 1401-6249 ; 467
ISBN 91-576-6495-1
[Doctoral thesis]

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Abstract

The c-Myc proto-oncogene encodes a transcription factor that controls genes involved in cell cycle regulation, cell growth, apoptosis and other cellular processes together with its partner Max. c-Myc has been shown to be altered in a wide variety of human tumors. This thesis focuses on post-translational regulation of Myc function. The aims was firstly to elucidate mechanisms of regulation of Myc degradation and components involved, and secondly to understand the mechanism(s) behind IFN-γ-induced inactivation of Myc. The c-Myc oncoprotein is short–lived phosphoprotein. We have found that Myc is tightly regulated via ubiquitin/proteasome-mediated turnover and that mutation of the Thr-58 phosphorylation site, which is frequently mutated in both in Burkitt’s lymphoma leads to stabilization of c-Myc. We have further established that the E3-ubiquitin ligase SCFSkp2 associates with c-Myc in late G1 and S-phase of the cell cycle, inducing not only ubiquitin-mediated degradation of c-Myc but surprisingly transcriptional activation of c-Myc target genes. Skp2 as well as proteasomal subunits were shown to be recruited to a Myc target promoter in vivo in a Myc-dependent manner. The second part of the thesis shows that the cytokine IFN-γ restore differentiation and cell cycle arrest in v-Myc expressing monocytic cells through inhibition of Myc-induced transcription, Myc DNA-binding and destabilization of Myc:Max heterodimers, correlating with dephosphorylation of Myc. We further found that IFN-γ reduces phosphorylation of Ser-62 and increases ubiquitin/proteasome-mediated degradation of Myc in a Ser-62 dependent manner.CycE/CDK2 was identified as a Ser-62 kinase in vivo and in vitro. IFN-γ-induced degradation and Ser-62 dephosphorylation correlated with inactivation of CDK2 through p27Kip1, which was shown to be required for this process. In conclusion, the thesis suggests that ubiquitin/proteasome-mediated turnover is an essential level of regulation of Myc function that may have important future implications for treatment of tumors with deregulated Myc expression.

Authors/Creators:Bahram, Fuad
Title:Post-translational regulation of Myc oncoprotein function
Year of publishing :September 2004
Volume:467
Number of Pages:62
Papers/manuscripts:
NumberReferences
ALLI. Bahram F, von der Lehr N, Cetinkaya C, Larsson LG. c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover. Blood. 2000 Mar 15;95(6):2104-10. II. von der Lehr N, Johansson S, Wu S, Bahram F, Castell A, Cetinkaya C, Hydbring P, Weidung I, Nakayama K, Nakayama KI, Soderberg O, Kerppola TK, Larsson LG. The F-box protein Skp2 participates in c-Myc proteosomal degradation and acts as a cofactor for c-Myc-regulated transcription. Mol. Cell. 2003 May;11(5):1189-200 III. Bahram F, Wu S, Oberg F, Luscher B, Larsson LG. Posttranslational regulations of Myc function in response to phorbol ester/interferon-gamma-induced differentiation of v-Myc-transformed U-937 monoblasts. Blood. 1999Jun1;93 (11):3900-12. IV. Fuad Bahram1, Natalie von der Lehr1, Richard Lilischkis2, Sara Johansson1 Bernhard Lüscher2 and Lars-Gunnar Larsson1 Interferon-gamma inhibits CycE/Cdk2-mediated phosphorylation of c-Myc via P27Kip1 resulting in increased Myc ubiquitylation and degradation.
Place of Publication:SLU
ISBN for printed version:91-576-6495-1
ISSN:1401-6249
Language:English
Publication Type:Doctoral thesis
Full Text Status:Public
Agris subject categories.:X Agricola extesions > X30 Life sciences
Subjects:Not in use, please see Agris categories
Agrovoc terms:transcription
Keywords:Myc, Skp2, p27Kip1, CycE/CDK2, ubiquitin/proteasome pathway, transcription, cell cycle, differentiation, and IFN-γ
URN:NBN:urn:nbn:se:slu:epsilon-282
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-282
ID Code:624
Department:(NL, NJ) > Dept. of Plant Biology and Forest Genetics (until 131231)
Deposited By: Fuad Bahram
Deposited On:15 Sep 2004 00:00
Metadata Last Modified:02 Dec 2014 10:06

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