ABSTRACT
Although ASXL1 mutations are frequently found in human diseases, including myeloid leukemia, the cell proliferation-associated function of ASXL1 is largely unknown. Here, we explored the molecular mechanism underlying the growth defect found in Asxl1-deficient mouse embryonic fibroblasts (MEFs). We found that Asxl1, through amino acids 371 to 655, interacts with the kinase domain of AKT1. In Asxl1-null MEFs, IGF-1 was unable to induce AKT1 phosphorylation and activation; p27Kip1, which forms a ternary complex with ASXL1 and AKT1, therefore remained unphosphorylated. Hypophosphorylated p27Kip1 is able to enter the nucleus, where it prevents the phosphorylation of Rb; this ultimately leads to the down-regulation of E2F target genes as confirmed by microarray analysis. We also found that senescence-associated (SA) genes were upregulated and that SA ß-gal staining was increased in Asxl1 -/- MEFs. Further, the treatment of an AKT inhibitor not only stimulated nuclear accumulation of p27Kip1 leading to E2F inactivation, but also promoted senescence. Finally, Asxl1 disruption augmented the expression of p16Ink4a as result of the defect in Asxl1-Ezh2 cooperation. Overall, our study provides the first evidence that Asxl1 both activates the AKT-E2F pathway and cooperates with Ezh2 through direct interactions at early embryonic stages, reflecting that Asxl1 disruption causes cellular senescence.
Subject(s)
Cellular Senescence , E2F Transcription Factors/antagonists & inhibitors , Embryo, Mammalian/pathology , Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors , Fibroblasts/pathology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Repressor Proteins/physiology , Animals , Cell Proliferation , Cells, Cultured , E2F Transcription Factors/genetics , E2F Transcription Factors/metabolism , Embryo, Mammalian/metabolism , Enhancer of Zeste Homolog 2 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Fibroblasts/metabolism , Mice , Mice, Knockout , Phosphorylation , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Reactive Oxygen Species/metabolism , Signal TransductionABSTRACT
PURPOSE: The purpose of this study was to identify the factors influencing sexual assertiveness in dating college students. METHODS: With a cross-sectional survey design, 468 college students who have had dating experiences were recruited and answered questionnaires. Data were analyzed using t-test, ANOVA with Scheffe? test, Pearson's correlation coefficients, and multiple regression. RESULTS: The sexual assertiveness of college students showed significant results positive correlations with self-assertiveness and negative correlations with traditional sexual attitude, gender role stereotypes. Significant predictors of sexual assertiveness were traditional sexual attitude, gender role stereotypes, and self-assertiveness. These variables explained 37% of the variance in sexual assertiveness. CONCLUSION: Findings suggest that it is important to identify and improve communication patterns in relation to sexual assertiveness. There is a need for sex education programs for college students that are relevant and effective.
