Phosphorylation regulates c-Myc's oncogenic activity in the mammary gland.
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-Myc(WT) or the c-Myc(T58A) or c-Myc(S62A) 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-Myc(WT) resulted in increased mammary gland density, but normal morphology and no tumors at the level expressed from the ROSA promoter. In contrast, c-Myc(T58A) expression yielded enhanced mammary gland density, hyperplastic foci, cellular dysplasia, and mammary carcinoma, associated with increased genomic instability and suppressed apoptosis relative to c-Myc(WT). Alternatively, c-Myc(S62A) 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.
Molecular and Medical Genetics Department, Oregon Health and Sciences University, Portland, Oregon, USA.
Xiaoyan
X
Wang
Melissa
M
Cunningham
Xiaoli
X
Zhang
Sara
S
Tokarz
Bryan
B
Laraway
Megan
M
Troxell
Rosalie C
RC
Sears
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018385:Centrosome / Q000378:metabolism / Q000473:pathology; D043171:Chromosomal Instability; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc
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