Modified p27 Kip1 is efficient in suppressing HER2-mediated tumorigenicity.
Cyclin-dependent kinase (CDK) inhibitor p27 Kip1, a haplo-insufficient tumor suppressor, is downregulated by oncogenic signal of HER2, a receptor tyrosine kinase oncogene. HER2 promotes mitogenic growth and transformation of cancer cells. HER2 signaling can enhance p27 Kip1 ubiquitination, thereby promoting p27 degradation and subsequent activation of CDK activity. p27 ubiquitination and degradation is enhanced by JAB1 binding as well as by phosphorylation on Thr187. In this study, we generated modified p27 proteins, which are mutated at Thr 187 or deleted at JAB1 binding domain. We applied these modified p27 genes as novel anticancer agents for HER2-overexpressing cells under the control of a tetracycline (tet)-regulated gene expression system. Induction of p27 T187A and p27 T187A DeltaJAB inhibits HER2-activated cell growth, CDK2 activity, cell proliferation, and transformation. Significantly, a modified protein (p27 T187ADeltaJAB) reduced the tumor volume in a HER2-overexpressing tumor model efficiently. These findings demonstrate the applicability of employing modified p27 proteins as a therapeutic intervention in HER2-overexpressing cancers.
Yang
Heng-Yin
HY
Department of Molecular and Cellular Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Yang
Huiling
H
Zhao
Ruiying
R
Lee
Mong-Hong
MH
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000075686:COP9 Signalosome Complex; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D006131:Growth Inhibitors / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008934:Mitogens / Q000502:physiology; D041681:NIH 3T3 Cells; D010447:Peptide Hydrolases / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D013912:Threonine / Q000235:genetics; D014162:Transfection
D000075686:COP9 Signalosome Complex; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006131:Growth Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008934:Mitogens; D010447:Peptide Hydrolases; D018719:Erb-b2 Receptor Tyrosine Kinases; D013912:Threonine; C501490:Cops5 protein, mouse