Rb-dependent cellular senescence, multinucleation and susceptibility to oncogenic transformation through PKC scaffolding by SSeCKS/AKAP12

Shin Akakura, Peter Nochajski, Lingqiu Gao, Paula Sotomayor, Sei Ichi Matsui, Irwin H. Gelman

Resultado de la investigación: Contribución a una revistaArtículo

44 Citas (Scopus)

Resumen

A subset of AKAPs (A Kinase Anchoring Proteins) regulate signaling and cytoskeletal pathways through the spaciotemporal scaffolding of multiple protein kinases (PK), such as PKC and PKA, and associations with the plasma membrane and the actin-based cytoskeleton. SSeCKS/Gravin/Akap12 expression is severely downregulated in many advanced cancers and exhibits tumor- and metastasis-suppressing activity. akap12-null (KO) mice develop prostatic hyperplasia with focal dysplasia, but the precise mechanism how Akap12 prevents oncogenic progression remains unclear. Here, we show that KO mouse embryonic fibroblasts (MEF) exhibit premature senescence marked by polyploidy and multinucleation, and by increased susceptibility to oncogenic transformation. Although p53 and Rb pathways are activated in the absence of Akap12, senescence is dependent on Rb. Senescence is driven by the activation of PKCα, which induces p16Ink4a/Rb through a MEK-dependent downregulation of Id1, and PKCδ, which downregulates Lats1/Warts, a mitotic exit network kinase required for cytokinesis. Our data strongly suggest that Akap12 controls Rb-mediated cell aging and oncogenic progression by directly scaffolding and attenuating PKCα/δ.

Idioma originalInglés
Páginas (desde-hasta)4656-4665
Número de páginas10
PublicaciónCell Cycle
Volumen9
N.º23
DOI
EstadoPublicada - 1 dic 2010

Áreas temáticas de ASJC Scopus

  • Biología molecular
  • Biología del desarrollo
  • Biología celular

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