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Title: Fbw7 promotes ubiquitin-dependent degradation of c-Myb: Involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb
Authors: Kitagawa, K.
Hiramatsu, Y.
Uchida, C. 
Isobe, T.
Hattori, T. 
Oda, T.
Shibata, K.
Nakamura, S.
Kikuchi, A.
Kitagawa, M.
Keywords: C-Myb
Issue Date: 25-Jun-2009
Citation: Kitagawa, K., Hiramatsu, Y., Uchida, C., Isobe, T., Hattori, T., Oda, T., Shibata, K., Nakamura, S., Kikuchi, A., Kitagawa, M. (2009-06-25). Fbw7 promotes ubiquitin-dependent degradation of c-Myb: Involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb. Oncogene 28 (25) : 2393-2405. ScholarBank@NUS Repository.
Abstract: Expression of oncoprotein c-Myb oscillates during hematopoiesis and hematological malignancies. Its quantity is not only regulated through transcriptional control but also through the ubiquitin-proteasome pathway, accompanied by phosphorylation, although the mechanisms are poorly understood. In this report, we tried to identify an E3 ubiquitin ligase, which targets c-Myb for ubiquitin-dependent degradation. We found that an F-box protein, Fbw7, interacted with c-Myb, which is mutated in numerous cancers. Fbw7 facilitated ubiquitylation and degradation of c-Myb in intact cells. Moreover, depletion of Fbw7 by RNA interference delayed turnover and increased the abundance of c-Myb in myeloid leukemia cells concomitantly, and suppressed the transcriptional level of γ-globin, which receives transcriptional repression from c-Myb. In addition, we analysed sites required for both ubiquitylation and degradation of c-Myb. We found that Thr-572 is critical for Fbw7-mediated ubiquitylation in mouse c-Myb using site-directed mutagenesis. Fbw7 recognized the phosphorylation of Thr-572, which was mediated by glycogen synthase kinase 3 (GSK3). In consequence, the c-Myb protein was markedly stabilized by the substitution of Thr-572 to Ala. These observations suggest that SCF Fbw7 ubiquitin ligase regulates phosphorylation-dependent degradation of c-Myb protein. © 2009 Macmillan Publishers Limited. All rights reserved.
Source Title: Oncogene
ISSN: 09509232
DOI: 10.1038/onc.2009.111
Appears in Collections:Staff Publications

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