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Substitution of Thr572 to Ala in mouse c-Myb attenuates progression of early erythroid differentiation

The expression level of transcription factor c-Myb oscillates during hematopoiesis. Fbw7 promotes ubiquitin-mediated degradation of c-Myb, which is dependent on phosphorylation of Thr572. To investigate the physiological relevance of Fbw7-mediated c-Myb degradation, we generated mutant mice carrying...

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Detalles Bibliográficos
Autores principales: Kitagawa, Kyoko, Uchida, Chiharu, Horiguchi, Ryo, Ohhata, Tatsuya, Sakai, Satoshi, Niida, Hiroyuki, Yasumoto, Shuhei, Handa, Yukino, Suzuki, Moena, Hashimoto, Masako, Tazawa, Toshiyasu, Yokochi, Yuta, Tsuji, Mayumi, Kitagawa, Masatoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463259/
https://www.ncbi.nlm.nih.gov/pubmed/32873855
http://dx.doi.org/10.1038/s41598-020-71267-5
Descripción
Sumario:The expression level of transcription factor c-Myb oscillates during hematopoiesis. Fbw7 promotes ubiquitin-mediated degradation of c-Myb, which is dependent on phosphorylation of Thr572. To investigate the physiological relevance of Fbw7-mediated c-Myb degradation, we generated mutant mice carrying c-Myb-T572A (TA). Homozygous mutant (TA/TA) mice exhibited a reduction in the number of peripheral red blood cells and diminished erythroblasts in bone marrow, presumably as a result of failure during erythroblast differentiation. We found that c-Myb high-expressing cells converged in the Lin(−)CD71(+) fraction, and the expression of c-Myb was higher in TA/TA mice than in wild-type mice. Moreover, TA/TA mice had an increased proportion of the CD71(+) subset in Lin(−) cells. The c-Myb level in the Lin(−)CD71(+) subset showed three peaks, and the individual c-Myb level was positively correlated with that of c-Kit, a marker of undifferentiated cells. Ultimately, the proportion of c-Myb(hi) subgroup was significantly increased in TA/TA mice compared with wild-type mice. These results indicate that a delay in reduction of c-Myb protein during an early stage of erythroid differentiation creates its obstacle in TA/TA mice. In this study, we showed the T572-dependent downregulation of c-Myb protein is required for proper differentiation in early-stage erythroblasts, suggesting the in vivo significance of Fbw7-mediated c-Myb degradation.