MicroRNA-34a (miR-

HR and hiring managers in the current study were not overly enthusiastic about people with disabilities as reliable and productive employees. ADA and job accommodations training might improve these managers' attitudes toward people with disabilities. Intervention at the senior management level should focus on changing company policies to include disability as part of the company's diversity efforts.

The`high risk' human papillomaviruses are associated with the development of anogenital carcinomas and their E6 and E7 genes possess immortalizing and transforming functions in several in vitro culture systems. Recently the E6 gene has also been shown to enhance the apoptosis of human mammary epithelial cells. To determine the apoptotic activity of these oncogenes in the natural host cell, we infected genital keratinocytes with retroviruses expressing either HPV-16 E6, E7, or both the E6 and E7 (E6/7) genes. Apoptosis was quantitated under normal growth conditions or when induced by tumor necrosis factor a/cycloheximide or sulfur mustard. In contrast to previous ®ndings with mammary epithelial cells, the E6 gene did not signi®cantly augment either spontaneous or induced apoptosis. E6 also did not suppress apoptosis in normal keratinocytes (despite dramatically reducing their p53 levels), suggesting that p53-independent events mediated this eect. In contrast, E7 increased both spontaneous and induced apoptosis as well as the cellular levels of p53 and p21 protein. Interestingly, coexpression of E6 abrogated E7-facilitated apoptosis by tumor necrosis factor a nearly completely, but had only a minor protective eect on sulfur mustard induced apoptosis in these cells, demonstrating at least in part the p53-dependence and -independence of these two apoptotic pathways. Finally, our results indicate that the apoptosis of normal and E7-expressing keratinocytes is dierentially aected by E6 expression and that E7, when unaccompanied by E6, sensitizes keratinocytes to apoptosis.

We show, for the first time, that the tumor suppressor PTEN can have tumor-promoting properties. We show that PTEN acquires these unexpected properties by enhancing gainof-function mutant p53 (mut-p53) protein levels. We find that PTEN restoration to cells harboring mut-p53 leads to induction of G 1 -S cell cycle progression and cell proliferation and to inhibition of cell death. Conversely, PTEN inhibition in cells expressing wild-type PTEN and mut-p53 leads to inhibition of cell proliferation and inhibition of in vivo tumor growth. We show the dependency of the tumor-promoting effects of PTEN on mut-p53 by showing that knockdown of mut-p53 expression inhibits or reverses the tumor-promoting effects of PTEN. Mechanistically, we show that PTEN expression enhances mut-p53 protein levels via inhibition of mutp53 degradation by Mdm2 and possibly also via direct protein binding. These findings describe a novel function of PTEN and have important implications for experimental and therapeutic strategies that aim at manipulating PTEN or p53 in human tumors. They suggest that the mutational status of PTEN and p53 should be considered to achieve favorable therapeutic outcomes. The findings also provide an explanation for the low frequency of simultaneous mutations of PTEN and p53 in human cancer.

The growth factor hepatocyte growth factor (HGF), also known as scatter factor, and its tyrosine kinase receptor c-Met play important roles in medulloblastoma malignancy. The transcription factor c-Myc is another contributor to the malignancy of these most common pediatric brain tumors. In the present study, we observed strong morphological similarities between medulloblastoma xenografts overexpressing HGF and medulloblastoma xenografts overexpressing c-Myc. We therefore hypothesized a biologically significant link between HGF/c-Met and c-Myc in medulloblastoma malignancy and studied the molecular and functional interactions between them. We found that HGF induces c-Myc mRNA and protein in established and primary medulloblastoma cells. HGF regulated c-Myc levels via transcriptional and posttranscriptional mechanisms as evidenced by HGF induction of c-Myc promoter activity and induction of c-Myc protein levels in the setting of inhibited transcription and translation. We also found that HGF induces cell cycle progression, cell proliferation, apoptosis and increase in cell size in a c-Myc-dependent manner. Activation of MAPK and PI3K, inhibition of GSK-3b and translocation of b-catenin to the nucleus as well as Tcf/Lef transcriptional activity were involved in mediating c-Myc induction by HGF. Induction of Cdk2 kinase activity was involved in mediating the cell cycle progression effects, and downregulation of Bcl-XL was involved in mediating the proapoptotic effects of HGF downstream of c-Myc. All molecules that mediated the effects of HGF on c-Myc expression, cell proliferation and apoptosis were expressed in human large-cell medulloblastoma tissues. We therefore established for the first time a functional cooperation between HGF/c-Met and c-Myc in human medulloblastoma and elucidated the molecular mechanisms of this cooperation. The findings provide a potential explanation for the high frequency of c-Myc overexpression in medulloblastoma and suggest a cooperative role for c-Met and c-Myc in large-cell anaplastic medulloblastoma formation.