Beta-catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development.
ABSTRACT Tumor progression is a multistep process in which proproliferation mutations must be accompanied by suppression of senescence. In melanoma, proproliferative signals are provided by activating mutations in NRAS and BRAF, whereas senescence is bypassed by inactivation of the p16(Ink4a) gene. Melanomas also frequently exhibit constitutive activation of the Wnt/beta-catenin pathway that is presumed to induce proliferation, as it does in carcinomas. We show here that, contrary to expectations, stabilized beta-catenin reduces the number of melanoblasts in vivo and immortalizes primary skin melanocytes by silencing the p16(Ink4a) promoter. Significantly, in a novel mouse model for melanoma, stabilized beta-catenin bypasses the requirement for p16(Ink4a) mutations and, together with an activated N-Ras oncogene, leads to melanoma with high penetrance and short latency. The results reveal that synergy between the Wnt and mitogen-activated protein (MAP) kinase pathways may represent an important mechanism underpinning the genesis of melanoma, a highly aggressive and increasingly common disease.
[show abstract] [hide abstract]
ABSTRACT: To ascertain if infectious mononucleosis is a risk factor for the development of multiple sclerosis (MS); and, if it is, whether its effect is close to or remote in time from the onset of MS. Analysis of database of linked abstracts of records of hospital admission and death. Health region in central southern England. Ratio of rate of MS in a cohort of people admitted to hospital with infectious mononucleosis to the rate in a comparison cohort. Considering all time intervals from admission with infection to admission with MS, there was a non-significant increase of risk of MS in the infectious mononucleosis cohort (rate ratio 2.17, 95% confidence intervals 0.79 to 4.77). At the interval of 10 years or more, there was a significant increase in risk of MS (rate ratio 4.01, 1.48 to 8.93). The mean time from infectious mononucleosis to first admission with MS was 14 years. This study adds support to the evidence that Epstein-Barr virus, the cause of infectious mononucleosis, is associated with MS. Its role is probably as an initiator of the disease process of MS, or as a contributor to its early development, rather than as an activator of latent, existing disease.Journal of Epidemiology & Community Health 01/2005; 58(12):1032-5. · 3.19 Impact Factor