Chronic mild stress leads to anxiety-like behavior and decreased p70 S6K1 activity in the hippocampus of male mice.

Major affective disorders are highly prevalent, however, current treatments are limited in their effectiveness due to a lack of understanding of underlying molecular mechanisms. Recent studies have shown that reduced activity of p70 S6 kinase 1 (S6K1), a downstream target of the mechanistic target of rapamycin complex 1 (mTORC1), is linked to anxiety-like behavior in both humans and rodents. The purpose of this study was to investigate the relationship between S6K1 and anxiety-like behavior following chronic mild stress (CMS) and drug-induced inhibition of S6K1. Following CMS, anxiety-like behavior was evaluated using an open field (OF) and elevated plus maze (EPM) in adult male C57/Bl6 mice. After behavior analysis, samples of the hippocampus were harvested for quantification of S6K1, S6 ribosomal protein, glycogen synthase kinase-3 ß (GSK3ß), and beta tubulin via western blot. Our results demonstrate that CMS mice exhibit anxiety-like behavior in the OF and EPM and reduced activity of S6K1 in the hippocampus (HPC). We measured phosphorylation levels of GSK3ß and found that GSK3ß phosphorylation was also reduced following CMS compared to control mice. Furthermore, pharmacological inhibition of S6K1 with PF-4708671 in male mice was sufficient to produce anxiety-like behavior in the OF and EPM. These results further support the significant role of S6K1 in the pathogenesis of anxiety and affective disorders.

AKT1E17K Activates Focal Adhesion Kinase and Promotes Melanoma Brain Metastasis.

Alterations in the PI3K/AKT pathway occur in up to 70% of melanomas and are associated with disease progression. The three AKT paralogs are highly conserved but data suggest they have distinct functions. Activating mutations of AKT1 and AKT3 occur in human melanoma but their role in melanoma formation and metastasis remains unclear. Using an established melanoma mouse model, we evaluated E17K, E40K, and Q79K mutations in AKT1, AKT2, and AKT3 and show that mice harboring tumors expressing AKT1E17K had the highest incidence of brain metastasis and lowest mean survival. Tumors expressing AKT1E17K displayed elevated levels of focal adhesion factors and enhanced phosphorylation of focal adhesion kinase (FAK). AKT1E17K expression in melanoma cells increased invasion and this was reduced by pharmacologic inhibition of either AKT or FAK. These data suggest that the different AKT paralogs have distinct roles in melanoma brain metastasis and that AKT and FAK may be promising therapeutic targets. IMPLICATIONS: This study suggests that AKT1E17K promotes melanoma brain metastasis through activation of FAK and provides a rationale for the therapeutic targeting of AKT and/or FAK to reduce melanoma metastasis.

A Nonsynonymous Variant in the GOLM1 Gene in Cutaneous Malignant Melanoma.

Background: Statistically significant linkage of melanoma to chromosome 9q21 was previously reported in a Danish pedigree resource and independently confirmed in Utah high-risk pedigrees, indicating strong evidence that this region contains a melanoma predisposition gene. Methods: Whole-exome sequencing of pairs of related melanoma case subjects from two pedigrees with evidence of 9q21 linkage was performed to identify the responsible predisposition gene. Candidate variants were tested for association with melanoma in an independent set of 454 unrelated familial melanoma case subjects and 396 unrelated cancer-free control subjects from Utah, and 1534 melanoma case subjects and 1146 noncancer control subjects from Texas (MD Anderson) via a two-sided Fisher exact test. Results: A rare nonsynonymous variant in Golgi Membrane Protein 1 (GOLM1), rs149739829, shared in two hypothesized predisposition carriers in one linked pedigree was observed. Segregation of this variant in additional affected relatives of the index carriers was confirmed. A statistically significant excess of carriers of the variant was observed among Utah case subjects and control subjects (odds ratio [OR] = 9.81, 95% confidence interval [CI] = 8.35 to 11.26, P < .001) and statistically significantly confirmed in Texas case subjects and control subjects (OR = 2.45, 95% CI = 1.65 to 3.25, P = .02). Conclusion: These findings support GOLM1 as a candidate melanoma predisposition gene.