ABSTRACT
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
Cyclin-dependent kinase inhibitor p2(Waf1/Cip1/Sdi1/CAP20) plays the key part in cell cycle arrest at the G1/S checkpoint in response to DNA damage, and is involved in the assembly of active cyclin-kinase complexes, in particular, cyclin D-Cdk4/6. Recent studies extended the range of known p21Waf1 functions. In addition to the cell-cycle control, p21Waf1 participates in important cell processes such as differentiation, senescence, and apoptosis. A balance of p21Waf1 functional activity seems to shift depending on the cell state (senescence, exposure to stress, expression of viral oncogenes). This is due to direct or indirect interaction with various modulators or to modification (phosphorylation, partial proteolysis) of p21Waf1. The review considers the structure of p21Waf1, its posttranslational modification, interactions with various cell or viral proteins, and their effects on the p21Waf1 function and the cell.
Subject(s)
Cyclins/physiology , Stress, Physiological/physiopathology , Animals , Cell Cycle/physiology , Cell Division/physiology , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/metabolism , Humans , Phosphorylation , Protein BindingABSTRACT
The capability of adenoviral oncoproteins E1A Ad2 and Ad12 to form complexes in vivo with cyclin-kinase inhibitor p21Waf1 has been analysed. The published data confirming direct interaction between E1A and p21Waf1 are insufficient. In the present work, a yeast two-hybrid SRS system was used to investigate the binding of different fragments of E1A Ad2 and Ad12 polypeptides with p21Waf1. We have shown that the full length product of 12S mRNA E1A Ad2 interacts weekly with p21Waf1, whereas the protein corresponding to 13S mRNA E1A Ad12 does not bind to cyclin-kinase inhibitor protein. Moreover, fragments 1-80 (Ad2), 1-29 (Ad12), 1-79 (Ad12), and 105-194 (Ad12) were able to interact with p21Waf1 to some extent. The difference between interacting regions of adenoviral proteins E1A Ad2/5 and Ad12 gives a new information about the mechanism of p21Waf1 functional inactivation and different transforming activity of Ad2/5 and Ad12.
