ABSTRACT
Conversion of intestinal stem cells into tumor-initiating cells is an early step in Apc(Min)-induced polyposis. Wild-type p53-induced phosphatase 1 (Wip1)-dependent activation of a DNA damage response and p53 has a permanent role in suppression of stem cell conversion, and deletion of Wip1 lowers the tumor burden in Apc(Min) mice. Here we show that cyclin-dependent kinase inhibitor 2a, checkpoint kinase 2, and growth arrest and DNA damage gene 45a (Gadd45a) exert critical functions in the tumor-resistant phenotype of Wip1-deficient mice. We further identified Gadd45a as a haploinsufficient gene in the regulation of Wip1-dependent tumor resistance in mice. Gadd45a appears to function through its ability to activate the Jnk-dependent signaling pathway that in turn is a necessary mediator of the proapoptotic functions of p53 that respond to activation of the ß-catenin signaling pathway. We propose that silencing of Gadd45a is sufficient to override p53 activation in the presence of active ß-catenin under conditions of an enhanced DNA damage response.
Subject(s)
Cell Cycle Proteins/metabolism , Nuclear Proteins/metabolism , Phosphoprotein Phosphatases/metabolism , Animals , Apoptosis , Cell Transformation, Neoplastic , Checkpoint Kinase 2 , Cyclin-Dependent Kinase Inhibitor p16/metabolism , DNA Repair , Genes, APC , Intestinal Polyposis/metabolism , Intestinal Polyposis/pathology , JNK Mitogen-Activated Protein Kinases/metabolism , Mice , Mice, Knockout , Phosphoprotein Phosphatases/deficiency , Phosphoprotein Phosphatases/genetics , Protein Phosphatase 2C , Protein Serine-Threonine Kinases/metabolism , Receptors, G-Protein-Coupled/metabolism , Signal Transduction , Stem Cells/metabolism , Tumor Suppressor Protein p53/metabolism , beta Catenin/metabolismABSTRACT
There is increasing evidence for the role of wild-type p53 induced phosphatase 1 (Wip1) phosphatase in the regulation of tumorigenesis. To evaluate Wip1 as a breast cancer oncogene, we generated a mouse strain with targeted expression of Wip1 to the breast epithelium. We found that these mice are prone to cancer when intercrossed with transgenics expressing the ErbB2 oncogene but not conditional knockouts for Brca2. This tumor-prone phenotype of Wip1 is fully eliminated through attenuation of proliferation by activating the MKK6/p38 mitogen-activated protein kinases (MAPK) cascade in mice bearing a constitutively active form of MKK6. We propose that Wip1 phosphatase operates within the MKK6/p38 MAPK signaling pathway to promote ErbB2-driven mammary gland tumorigenesis.
Subject(s)
MAP Kinase Kinase 6/physiology , Mammary Neoplasms, Experimental/enzymology , Neoplasm Proteins/physiology , Phosphoprotein Phosphatases/physiology , Receptor, ErbB-2/physiology , p38 Mitogen-Activated Protein Kinases/physiology , Animals , Female , Humans , MAP Kinase Signaling System/genetics , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Knockout , Mice, Transgenic , Neoplasm Proteins/deficiency , Neoplasm Proteins/genetics , Phosphoprotein Phosphatases/deficiency , Phosphoprotein Phosphatases/genetics , Protein Phosphatase 1 , Protein Phosphatase 2CABSTRACT
The hepatitis delta virus (HDV) is an RNA containing virus that requires hepatitis B virus (HBV) to supply the envelope proteins. HDV only infect man in the presence of HBV, either as a coinfection or as superinfection in HBV carriers. In the presence of hepatitis B infection, the HDV may cause more severe liver damage than that caused by the hepatitis B virus alone. HDV infection was studied in 44 HBsAg positive serum samples collected from male intravenous drug users sent for screening to the Blood Services Centre (BSC), Hospital Kuala Lumpur (HKL) between 1990 and 1992. The majority (39) were in the 20 to 39 age group. The youngest was 19 years old and the oldest was 61 years old. There were 25 Malays, 13 Chinese, five Indians and one Albanian. Anti hepatitis delta antibody (Anti-HDV) was detected in 15 out of 44 (34%) of the drug addicts. These results shows an increased in delta infection in HBsAg positive intravenous drug addicts compared to the surveillance results in 1985 when no delta antibodies were detected, and the 1986 and 1989 surveillance which showed 17.8% and 20% delta antibody positivity respectively.
