Activation of Grm1 expression by mutated BRaf (V600E) in vitro and in vivo
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Ho-Chung Chen1,*, Jairo Sierra1,2,*, Lumeng Jenny Yu1,*, Robert Cerchio Jr.1,3, Brian A. Wall1,4, James Goydos2,5 and Suzie Chen1,2,3,5
1Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway 08854, NJ, USA
2Rutgers-GSBS at Robert Wood Johnson Medical School, Piscataway 08854, NJ, USA
3Pharmacology and Toxicology Graduate Program, Rutgers University, Piscataway 08854, NJ, USA
4Global Product Safety, Colgate-Palmolive Company, Piscataway 08854, NJ, USA
5Rutgers Cancer Institute of New Jersey, New Brunswick 08903, NJ, USA
*These authors contributed equally to this work
Suzie Chen, email: [email protected]
Keywords: mutated BRaf (V600E); Grm1; melanoma; senescence; p15
Received: September 27, 2017 Accepted: December 08, 2017 Published: December 23, 2017
Our laboratory previously showed that ectopic expression of Grm1 is sufficient to induce spontaneous melanoma formation with 100% penetrance in transgenic mouse model, TG-3, which harbors wild-type BRaf. Studies identified Grm1 expression in human melanoma cell lines and primary to secondary metastatic melanoma biopsies having wild-type or mutated BRaf, but not in normal melanocytes or benign nevi. Grm1 expression was detected in tissues from mice genetically engineered with inducible melanocyte-specific BRafV600E. Additionally, stable clones derived from introduction of exogenous BRafV600E in mouse melanocytes also showed Grm1 expression, which was not detected in the parental or empty vector-derived cells, suggesting that expression of BRafV600E could activate Grm1 expression. Despite aberrant Grm1 expression in the inducible, melanocyte-specific BRafV600E mice, no tumors formed. However, in older mice, the melanocytes underwent senescence, as demonstrated previously by others. It was proposed that upregulated p15 and TGFβ contributed to the senescence phenotype. In contrast, in older TG-3 mice the levels of p15 and TGFβ remained the same or lower. Taken together, these results suggest the temporal regulation on the expression of “oncogenes” such as Grm1 or BRafV600E is critical in the future fate of the cells. If BRafV600E is turned on first, Grm1 expression can be induced, but this is not sufficient to result in development of melanoma; the cells undergo senescence. In contrast, if ectopic expression of Grm1 is turned on first, then regardless of wild-type or mutated BRaf in the melanocytes melanoma development is the consequence.
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