p27 deficiency is associated with migration defects in PDGF-expressing gliomas in vivo.
p27(Kip1) is a cyclin dependent kinase inhibitor that functions as a tumor suppressor in a variety of different cancers. While p27 has a well established role in regulating the cell cycle, it has also been shown to regulate cellular migration by influencing the activation state of the small GTPase RhoA. We recently demonstrated that loss of p27 enhances tumor progression and leads to a dramatic decrease in survival in PDGF-induced oligodendrogliomas. Here we show that p27 deficient PDGF-expressing glial cells contained elevated levels of Rho-GTP and were less migratory than wild type cells. Migration defects in p27 deficient cells were rescued by either Rho kinase inhibition or expression of p27 or CK(-), a mutant of p27 that cannot bind cyclins/cdks. The RCAS/tv-a retroviral system was used to specifically induce PDGF-expressing gliomas in mice. Many of the p27 deficient mice died earlier than wild type mice and displayed hydrocephalus which was associated with periventricular tumors that failed to invade the normal brain parenchyma. Invasion failure was reversed by co-expression of PDGF with either the GAP domain of p190(RhoGAP), a negative regulator of Rho, or p27, or CK(-). These results suggest that p27 mediated regulation of the Rho pathway is cell cycle independent and demonstrate for the first time a migration defect in cancer cells that is associated with p27 deficiency in vivo in a mouse tumor model.
See
Wendy L
WL
Program in Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Heinberg
Adina R
AR
Holland
Eric C
EC
Resh
Marilyn D
MD
D000577:Amides / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D004195:Disease Models, Animal; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000577:Amides; D016213:Cyclins; D010982:Platelet-Derived Growth Factor; D011725:Pyridines; C108830:Y 27632; D050760:Cyclin-Dependent Kinase Inhibitor p27; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein