26 321

Cited 0 times in

The PI3K-Akt mediates oncogenic Met-induced centrosome amplification and chromosome instability.

Nam, HJ; Chae, S; Jang, SH; Cho, H; Lee, JH
Carcinogenesis, 31(9):1531-1540, 2010
Journal Title
The oncogenic ability of aberrant hepatocyte growth factor receptor (Met) signaling is thought to mainly rely on its mitogenic and anti-apoptotic effects. Recently, however, cumulating evidences suggest that genomic instability may be a crucial factor in tumorigenesis. Here, we address whether oncogenic Met receptor is linked to the centrosome abnormality and genomic instability. We showed that expression of the constitutive active Met (CA-Met) induced supernumerary centrosomes probably due to deregulated centrosome duplication, which was accompanied with multipolar spindle formation and aneuploidy. Interestingly, LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, significantly suppressed the appearance of supernumerary centrosomes. Moreover, knockdown of Akt with small interfering RNAs and overexpression of phosphatase and tensin homolog or dominant-negative Akt abrogated supernumerary centrosome formation, evidencing the involvement of PI3K signaling. We further showed that expression of CA-Met significantly increased aneuploidy in p53(-/-) HCT116 cells, but not in p53(+/+) HCT116 cells, indicating that the ability of CA-Met to induce chromosomal instability (CIN) phenotype is related with p53 status. Together, our data demonstrate that aberrant hepatocyte growth factor/Met signaling induces centrosome amplification and CIN via the PI3K-Akt pathway, providing an example that oncogenic growth factor signals prevalent in a wide variety of cancers have cross talks to centrosome abnormality and CIN.
MeSH terms
1-Phosphatidylinositol 4-Kinase/metabolism*Blotting, WesternCell CycleCell ProliferationCentrosome/physiology*Chromones/pharmacologyChromosomal Instability*Colonic Neoplasms/metabolismColonic Neoplasms/pathologyEnzyme InhibitorsFlow CytometryFluorescent Antibody TechniqueHela CellsHumansMitosisMorpholines/pharmacologyPhosphatidylinositol 3-Kinases/antagonists & inhibitorsPhosphatidylinositol 3-Kinases/metabolism*Proto-Oncogene Proteins c-akt/antagonists & inhibitorsProto-Oncogene Proteins c-akt/metabolism*Proto-Oncogene Proteins c-met/physiology*RNA, Small Interfering/pharmacologyReceptors, Growth Factor/physiology*Tumor Suppressor Protein p53/geneticsTumor Suppressor Protein p53/metabolism
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
Journal Papers > Research Organization > Institute for Medical Sciences
AJOU Authors
채, 선영조, 혜성이, 재호
Full Text Link
RIS (EndNote)
XLS (Excel)


해당 아이템을 이메일로 공유하기 원하시면 인증을 거치시기 바랍니다.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.