Phosphorylation regulates c-Myc's oncogenic activity in the mammary gland

Xiaoyan Wang, Melissa Cunningham, Xiaoli Zhang, Sara Tokarz, Bryan Laraway, Megan Troxell, Rosalie C. Sears

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

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 3 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.

Original languageEnglish (US)
Pages (from-to)925-936
Number of pages12
JournalCancer Research
Volume71
Issue number3
DOIs
StatePublished - Feb 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Wang, X., Cunningham, M., Zhang, X., Tokarz, S., Laraway, B., Troxell, M., & Sears, R. C. (2011). Phosphorylation regulates c-Myc's oncogenic activity in the mammary gland. Cancer Research, 71(3), 925-936. https://doi.org/10.1158/0008-5472.CAN-10-1032