Abstract
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.
Highlights
The HER-2/neu oncogene encodes a growth receptor tyrosine kinase, and amplification/overexpression of the human HER-2/neu gene are frequently found in human cancers, including breast, ovarian, lung, gastric, and oral cancers [1,2,3]
Because many cancers with the overexpression of HER2/neu overlap with those affected by reduced p27 expression, we studied the link between HER-2/neu oncogenic signals and p27 regulation
HER-2/neu Overexpression/Activation Results in Reduced p27 Expression—To investigate whether HER-2/neu affects the expression of p27, we used NIH3T3 cells, B104 –1-1 cells [18], MCF7, and HER18 cells [19] to examine the role of HER-2/neu signaling in regulating the protein level of p27 by immunoblotting
Summary
The HER-2/neu oncogene ( named c-erbB-2) encodes a growth receptor tyrosine kinase, and amplification/overexpression of the human HER-2/neu gene are frequently found in human cancers, including breast, ovarian, lung, gastric, and oral cancers [1,2,3]. P27, a CIP/KIP member, encodes a cyclin-dependent kinase inhibitor that causes G1 arrest by inhibiting the activities of G1cyclin-CDKs. As a negative regulator of the cell cycle, p27 is a new class of tumor suppressor and is haplo-insufficient in tumor suppression [5, 6]. Because p27 inhibits cyclin-CDK in a dosage-dependent manner to control cell cycle progression [15, 16], it is conceivable that decreased expression of p27 may result in abnormal cell proliferation in these cancers. This study provides an important mechanism link between two prognostic markers in cancers
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