Oncogenic signals of HER-2/neu in regulating the stability of the cyclin-dependent kinase inhibitor p27.
Overexpression and activation of HER-2/neu, a proto-oncogene, play a pivotal role in cancer formation. Strong expression of HER-2/neu in cancers has been associated with poor prognosis. Reduced expression of p27(Kip1), a cyclin-dependent kinase inhibitor, correlates with poor clinical outcome in many types of carcinomas. Because many cancers with the overexpression of HER-2/neu overlap with those affected by reduced p27 expression, we studied the link between HER-2/neu oncogenic signals and p27 regulation. We found that down-regulation of p27 correlates with HER-2/neu overexpression. To address the molecular mechanism of this inverse correlation, we found that reduction of p27 is caused by enhanced ubiquitin-mediated degradation, and the HER-2/Grb2/MAPK pathway is involved in the decrease of p27 stability. Also, HER-2/neu activity causes mislocation of p27 and Jun activation domain-binding protein 1 (JAB1), an exporter of p27, into the cytoplasm, thereby facilitating p27 degradation. These results reveal that HER-2/neu signals reduce p27 stability and thus present potential points for therapeutic intervention in HER-2/neu-associated cancers.
Yang
H Y
HY
Departments of Molecular Cellular Oncology and Surgical Oncology, Breast Cancer Research Program, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Zhou
B P
BP
Hung
M C
MC
Lee
M H
MH
D016475:3T3 Cells; D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D018734:Genes, erbB-2; D006801:Humans; D007700:Kinetics; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D011494:Protein Kinases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins / Q000378:metabolism
D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D008869:Microtubule-Associated Proteins; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; C493961:Cdkn1b protein, mouse; C000715470:MAS1 protein, human; C102333:histone H1 kinase