p27 Kip1 inhibits HER2/neu-mediated cell growth and tumorigenesis.
HER2/neu, a receptor tyrosine kinase oncogene, promotes mitogenic growth and transformation of cancer cells. We previously identified that its oncogenic signals down-regulate the cyclin-dependent kinase inhibitor p27 Kip1, which is defined as a haplo-insufficient tumor suppressor. Here, we applied the human p27 gene as a novel anticancer agent for HER2/neu-overexpressing cells under the control of a tetracycline (tet)-regulated gene expression system. Overexpression of p27 inhibits HER2/neu-activated CDK2 activity, cell proliferation, and transformation. Most significantly for clinical application, p27 expression in HER2/neu-overexpressing cells can be regulated in vivo and reduce the tumor volume in a tumor model. The findings demonstrate the applicability of employing p27 in HER2/neu-associated cancer gene therapy.
Yang
H Y
HY
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, TX 77030, USA.
Shao
R
R
Hung
M C
MC
Lee
M H
MH
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004318:Doxycycline / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005260:Female; D016193:G1 Phase; D015870:Gene Expression; D051379:Mice; D008819:Mice, Nude; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D013752:Tetracycline / Q000378:metabolism / Q000494:pharmacology
D018844:Cyclin-Dependent Kinases; D004318:Doxycycline; D004791:Enzyme Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D013752:Tetracycline