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Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion.

ABSTRACT: Isoform A of phosphatidylinositol 3-kinase enhancer (PIKE-A) is a newly identified prooncogenic factor that has been implicated in cancer cell growth. How PIKE-A activity is regulated in response to growth signal is poorly understood. Here, we demonstrate that cyclin dependent kinase 5 (Cdk5), a protein known to function mainly in postmitotic neurons, directly phosphorylates PIKE-A at Ser-279 in its GTPase domain in glioblastoma cells. This phosphorylation event stimulates PIKE-A GTPase activity and the activity of its downstream effector Akt. Growth signal activates Cdk5 and results in a Cdk5-dependent accumulation of phosphorylated PIKE-A and activation of Akt in the nucleus. Furthermore, PIKE-A phosphorylation and Cdk5 are increased in human glioblastoma specimens. Phosphorylation of PIKE-A by Cdk5 mediates growth factor-induced migration and invasion of human glioblastoma cells. Together, these findings identify PIKE as the first Cdk5 target in cancer cells, revealing a previously undescribed regulatory mechanism that mediates growth signal-induced activation of PIKE-A/Akt and tumor invasion.

SUBMITTER: Liu R

PROVIDER: S-EPMC2396674 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion.

Liu Ren R Tian Bo B Gearing Marla M Hunter Stephen S Ye Keqiang K Mao Zixu Z

Proceedings of the National Academy of Sciences of the United States of America 20080516 21

Isoform A of phosphatidylinositol 3-kinase enhancer (PIKE-A) is a newly identified prooncogenic factor that has been implicated in cancer cell growth. How PIKE-A activity is regulated in response to growth signal is poorly understood. Here, we demonstrate that cyclin dependent kinase 5 (Cdk5), a protein known to function mainly in postmitotic neurons, directly phosphorylates PIKE-A at Ser-279 in its GTPase domain in glioblastoma cells. This phosphorylation event stimulates PIKE-A GTPase activity ...[more]

PMID: 18487454

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Project description:BackgroundGlioblastoma (GBM) is one of the most aggressive and malignant tumor types. Despite treatment advances, GBM pathogenesis still remains largely unknown. MATN1-AS1, an intron-retained long non-coding RNA (lncRNA), has been implicated in GBM development. However, the underlying mechanism has not been identified. This study aimed to examine MATN1-AS1 expression and uncover its role in GBM.MethodsLncRNAs with low expression levels were selected by analyzing brain glioma-related genes. The relative mRNA level of MATN1-AS1 was quantified using RT-qPCR in 75 GBM tumors and 10 normal brain tissues. Overall survival was assessed using the Kaplan-Meier method. RT-qPCR and immunoblotting analysis were carried out to assess the levels of MATN1-AS1, RELA, ERK1/2, Bcl-2, Bax, survivin, and MMP-9 in GBM cells. Biological functions of MATN1-AS1 in GBM tumors were measured both in vivo and in vitro. The mechanism of RELA regulation by MATN1-AS1 was detected using RNA pull-down, RNA-binding protein immunoprecipitation, chromatin immunoprecipitation, and the dual luciferase reporter gene assay.ResultsMATN1-AS1 was the most downregulated lncRNA in GBM and was correlated with a shorter survival time and poorer prognosis of GBM patients. Conversely, RELA was increased in GBM tumor tissues and negatively correlated with MATN1-AS1 expression. MATN1-AS1 over-expression or siRNA-RELA knockdown resulted in downregulation of mRNA and protein levels of RELA, ERK1/2, Bcl-2, survivin, and MMP-9; reduced cell proliferation and invasion; increased Bax mRNA and protein levels; and enhanced cellular apoptosis. MATN1-AS1 bound to E2F6, which negatively targeted RELA. Furthermore, MATN1-AS1 over-expression in GBM cells resulted in significant inhibition of tumor growth in vivo.ConclusionsUpregulation of the lncRNA MATN1-AS1 inhibited GBM cell proliferation and invasion through inhibition of RELA via E2F6 and suppression of the MAPK signaling pathway. MATN1-AS1 might be an underlying therapeutic target for GBM.

Dataset Information

Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion.

Publications

Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion.

Similar Datasets

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