Phosphorylation regulates c-Myc's oncogenic activity in the mammary gland.
Phosphorylation regulates c-Myc's oncogenic activity in the mammary gland.
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DOI：
10.1158/0008-5472.can-10-1032
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发表时间：
2011-02-01
期刊：
影响因子：
11.2
通讯作者：
Sears RC
中科院分区：
文献类型：
--
作者：
Wang X;Cunningham M;Zhang X;Tokarz S;Laraway B;Troxell M;Sears RC
Expression of the c-Myc oncoprotein is affected by conserved Threonine 58 (T58) and Serine 62 (S62) phosphorylation sites that help to regulate c-Myc protein stability, and altered ratios of T58 and S62 phosphorylation have been observed in human cancer. Here, we report the development of three unique c-myc knock-in mice that conditionally express either c-MycWT, or the c-MycT58A or c-MycS62A phosphorylation mutant, from the constitutively active ROSA26 locus in response to Cre recombinase to study the role of these phosphorylation sites in vivo. Using a mammary-specific Cre model, we found that expression of c-MycWT resulted in increased mammary gland density but normal morphology and no tumors at the level expressed from the ROSA promoter. In contrast, c-MycT58A expression yielded enhanced mammary gland density, hyperplastic foci, cellular dysplasia, and mammary carcinoma, associated with increased genomic instability and suppressed apoptosis relative to c-MycWT. Alternatively, c-MycS62A expression reduced mammary gland density relative to control glands, and this was associated with increased genomic instability and normal apoptotic function. Our results indicate that specific activities of c-Myc are differentially affected by T58 and S62 phosphorylation. This model provides a robust platform to interrogate the role that these phosphorylation sites play in c-Myc function during development and tumorigenesis.
