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Updated: Jun 13, 2026
Induction of Protein Deletion Through In Utero Electroporation to Define Deficits in Neuronal Migration in Transgenic Models
Published on: January 12, 2015
p27 deficiency is associated with migration defects in PDGF-expressing gliomas in vivo
Wendy L See1, Adina R Heinberg, Eric C Holland
1Program in Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Abstract:
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.
Insights
Loss of p27(Kip1), a tumor suppressor, impairs glial cell migration and tumor invasion in mice. This cell cycle-independent effect is linked to the RhoA pathway, impacting cancer progression and survival.
Area of Science:
- Oncology
- Cell Biology
- Neuroscience
Background:
- p27(Kip1) is a cyclin-dependent kinase inhibitor and tumor suppressor.
- p27 regulates cell cycle and has been implicated in cellular migration via the RhoA pathway.
- Loss of p27 has been linked to enhanced tumor progression and reduced survival in PDGF-induced oligodendrogliomas.
Purpose of the Study:
- To investigate the role of p27 in regulating glial cell migration and tumor invasion in vivo.
- To determine if p27-mediated regulation of the Rho pathway is cell cycle-dependent or independent.
- To identify therapeutic targets for reversing migration defects in p27-deficient tumors.
Main Methods:
- Utilized the RCAS/tv-a retroviral system to induce PDGF-expressing gliomas in mice.
- Assessed RhoA activation (Rho-GTP levels) in p27-deficient and wild-type glial cells.
- Evaluated the effects of Rho kinase inhibition, p27 re-expression, and CK(-) expression on cell migration.
- Analyzed tumor invasion and survival rates in p27-deficient and wild-type mice.
Main Results:
- p27-deficient glial cells exhibited elevated Rho-GTP levels and reduced migratory capacity.
- Migration defects were rescued by Rho kinase inhibition or expression of p27 or CK(-).
- p27-deficient mice showed impaired tumor invasion and increased hydrocephalus.
- Invasion failure was reversed by co-expressing PDGF with p190(RhoGAP) GAP domain, p27, or CK(-).
Conclusions:
- p27 regulates glial cell migration and tumor invasion through a cell cycle-independent mechanism involving the Rho pathway.
- p27 deficiency leads to impaired tumor cell migration and invasion in vivo.
- Targeting the Rho pathway or restoring p27 function may be potential therapeutic strategies for oligodendrogliomas.
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