Regulation of Cdk7 activity through a phosphatidylinositol (3)-kinase/PKC-ι-mediated signaling cascade in glioblastoma.
The objective of this research was to study the potential function of protein kinase C (PKC)-ι in cell cycle progression and proliferation in glioblastoma. PKC-ι is highly overexpressed in human glioma and benign and malignant meningioma; however, little is understood about its role in regulating cell proliferation of glioblastoma. Several upstream molecular aberrations and/or loss of PTEN have been implicated to constitutively activate the phosphatidylinositol (PI) (3)-kinase pathway. PKC-ι is a targeted mediator in the PI (3)-kinase signal transduction repertoire. Results showed that PKC-ι was highly activated and overexpressed in glioma cells. PKC-ι directly associated and phosphorylated Cdk7 at T170 in a cell cycle-dependent manner, phosphorylating its downstream target, cdk2 at T160. Cdk2 has a major role in inducing G(1)-S phase progression of cells. Purified PKC-ι phosphorylated both endogenous and exogenous Cdk7. PKC-ι downregulation reduced Cdk7 and cdk2 phosphorylation following PI (3)-kinase inhibition, phosphotidylinositol-dependent kinase 1 knockdown as well as PKC-ι silencing (by siRNA treatment). It also diminished cdk2 activity. PKC-ι knockdown inhibited overall proliferation rates and induced apoptosis in glioma cells. These findings suggest that glioma cells may be proliferating through a novel PI (3)-kinase-/PKC-ι/Cdk7/cdk2-mediated pathway.
James A. Haley Veteran's Hospital, 13000 Bruce B. Downs Boulevard, Tampa, FL 33612, USA.
Shraddha R
SR
Desai
Prajit P
PP
Pillai
Rekha S
RS
Patel
Andrea N
AN
McCray
Hla Y
HY
Win-Piazza
Mildred E
ME
Acevedo-Duncan
D017209:Apoptosis; D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D005909:Glioblastoma / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000502:physiology*; D000095043:Cyclin-Dependent Kinase-Activating Kinase; D000099293:Protein Kinase C-lambda
D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D000095043:Cyclin-Dependent Kinase-Activating Kinase; D000099293:Protein Kinase C-lambda; C495894:CDK2 protein, human; C000722416:CDK7 protein, human