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 pivota l role in cancer formation. Strong expression of HER-2/neu in cancers has b een associated with poor prognosis. Reduced expression of p27(Kip1), a cycl in-dependent kinase inhibitor, correlates with poor clinical outcome in man y 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 addres s the molecular mechanism of this inverse correlation, we found that reduct ion of p27 is caused by enhanced ubiquitin-mediated degradation, and the HE R-2/Grb2/MAPK pathway is involved in the decrease of p27 stability. Also, H ER-2/neu activity causes mislocation of p27 and Jun activation domain-bindi ng protein 1 (JAB1), an exporter of p27, into the cytoplasm, thereby facili tating p27 degradation. These results reveal that HER-2/neu signals reduce p27 stability and thus present potential points for therapeutic interventio n in HER-2/neu-associated cancers.