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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732kB |
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 | ||||
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Title: | Post-translational regulation of Myc oncoprotein function | ||||
Year of publishing : | September 2004 | ||||
Number: | 467 | ||||
Number of Pages: | 62 | ||||
Papers/manuscripts: |
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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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