Somatic p16INK4a loss accelerates melanomagenesis

Abstract

Loss of p16INK4a–RB and ARF–p53 tumor suppressor pathways, as well as activation of RAS–RAF signaling, is seen in a majority of human melanomas. Although heterozygous germline mutations of p16INK4a are associated with familial melanoma, most melanomas result from somatic genetic events: often p16INK4a loss and N-RAS or B-RAF mutational activation, with a minority possessing alternative genetic alterations such as activating mutations in K-RAS and/or p53 inactivation. To generate a murine model of melanoma featuring some of these somatic genetic events, we engineered a novel conditional p16INK4a-null allele and combined this allele with a melanocyte-specific, inducible CRE recombinase strain, a conditional p53-null allele and a loxP-stop-loxP activatable oncogenic K-Ras allele. We found potent synergy between melanocyte-specific activation of K-Ras and loss of p16INK4a and/or p53 in melanomagenesis. Mice harboring melanocyte-specific activated K-Ras and loss of p16INK4a and/or p53 developed invasive, unpigmented and nonmetastatic melanomas with short latency and high penetrance. In addition, the capacity of these somatic genetic events to rapidly induce melanomas in adult mice suggests that melanocytes remain susceptible to transformation throughout adulthood.

Expression of p16INK4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

“…Toward that end, we utilized Cre recombinase to eliminate exon 1α of p16 INK4a in chondrocytes in vivo at skeletal maturity using a previously reported floxed p16 INK4a allele (p16 L ; Monahan et al., 2010) and an inducible, chondrocyte‐specific Aggrecan Cre driver ( Acan tm1(cre/ERT2)Crm ; Henry et al., 2009). A loxP‐stop‐loxP ZsGreen fluorescent reporter allele was also included in a subset of mice to facilitate fluorescent activated cell sorting (FACS) of chondrocytes that had undergone Cre‐mediated recombination.…”

“…The Acan tm1(cre/ERT2)Crm allele (Henry et al., 2009) (received from Dr. Benoit de Crombugghe, now available as stock #019148; Jackson Labs, Bar Harbor, ME, USA) was crossed to a p16 L conditional allele (Monahan et al., 2010). For OA studies with p16 INK4a intact ( Acan tm1(cre/ERT2)Crm p16 INK4a+/+ ) and p16 INK4a loss ( Acan tm1(cre/ERT2)Crm p16 L/L ) cohorts, male mice of C57BL/6 background were used due to the known development of hindlimb OA.…”

Transcriptional regulation of cellular senescence

“…Ink4a in some situations, including the progression of colorectal cancers and melanoma (Bennecke et al, 2010;Carragher et al, 2010;Monahan et al, 2010), Interestingly, no evidence to date supports the notion that in human cells, like in mouse cells, p14…”

New Drug Combination Strategies in Melanoma: Current Status and Future DirectionsNew Drug Combination Strategies in Melanoma: Current Status and Future Directions

“…The p16/cyclin D/CDK4/6/RB protein pathway (CDK4 pathway) is dysregulated in 90% of melanomas (66,67). Furthermore, activation of the CDK4 pathway cooperates with mutant BRAF or NRAS in transformation of melanocytes (68,69). MAPK pathway also enhances CDK4 signaling through increasing cyclin D1 expression.…”