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KAP regulates ROCK2 and Cdk2 in an RNA-activated glioblastoma invasion pathway.

Abstract
Aberrant splicing of the cyclin-dependent kinase-associated phosphatase, KAP, promotes glioblastoma invasion in a Cdc2-dependent manner. However, the mechanism by which this occurs is unknown. Here we show that miR-26a, which is often amplified in glioblastoma, promotes invasion in phosphatase and tensin homolog (PTEN)-competent and PTEN-deficient glioblastoma cells by directly downregulating KAP expression. Mechanistically, we find that KAP binds and activates ROCK2. Thus, RNA-mediated downregulation of KAP leads to decreased ROCK2 activity and this, in turn, increases Rac1-mediated invasion. In addition, the decrease in KAP expression activates the cyclin-dependent kinase, Cdk2, and this directly promotes invasion by increasing retinoblastoma phosphorylation, E2F-dependent Cdc2 expression and Cdc2-mediated inactivation of the actomyosin inhibitor, caldesmon. Importantly, glioblastoma cell invasion mediated by this pathway can be antagonized by Cdk2/Cdc2 inhibitors in vitro and in vivo. Thus, two distinct RNA-based mechanisms activate this novel KAP/ROCK2/Cdk2-dependent invasion pathway in glioblastoma.
AuthorsH Li, X Jiang, Y Yu, W Huang, H Xing, N Y Agar, H W Yang, B Yang, R S Carroll, M D Johnson
JournalOncogene (Oncogene) Vol. 34 Issue 11 Pg. 1432-41 (Mar 12 2015) ISSN: 1476-5594 [Electronic] England
PMID24704824 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Calmodulin-Binding Proteins
  • Cyclin-Dependent Kinase Inhibitor Proteins
  • E2F Transcription Factors
  • MIRN26A microRNA, human
  • MicroRNAs
  • RAC1 protein, human
  • RNA, Small Interfering
  • Retinoblastoma Protein
  • Actomyosin
  • ROCK2 protein, human
  • rho-Associated Kinases
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • CDKN3 protein, human
  • Dual-Specificity Phosphatases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • rac1 GTP-Binding Protein
Topics
  • Actomyosin (antagonists & inhibitors)
  • Brain Neoplasms (pathology)
  • CDC2 Protein Kinase
  • Calmodulin-Binding Proteins (antagonists & inhibitors)
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 2 (antagonists & inhibitors, genetics, metabolism)
  • Cyclin-Dependent Kinase Inhibitor Proteins (biosynthesis, genetics, metabolism)
  • Cyclin-Dependent Kinases (antagonists & inhibitors, biosynthesis)
  • Dual-Specificity Phosphatases (biosynthesis, genetics, metabolism)
  • E2F Transcription Factors (physiology)
  • Enzyme Activation
  • Glioblastoma (pathology)
  • Humans
  • MicroRNAs (antagonists & inhibitors, genetics, physiology)
  • Neoplasm Invasiveness
  • PTEN Phosphohydrolase (metabolism)
  • Phosphorylation
  • Protein Binding
  • RNA Interference
  • RNA, Small Interfering
  • Retinoblastoma Protein (metabolism)
  • rac1 GTP-Binding Protein (physiology)
  • rho-Associated Kinases (metabolism)

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