Rb-dependent cellular senescence, multinucleation and susceptibility to oncogenic transformation through PKC scaffolding by SSeCKS/AKAP12
Rb-dependent cellular senescence, multinucleation and susceptibility to oncogenic transformation through PKC scaffolding by SSeCKS/AKAP12
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DOI：
10.4161/cc.9.23.13974
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发表时间：
2010-12-01
期刊：
影响因子：
4.3
通讯作者：
Gelman, Irwin H.
中科院分区：
文献类型：
--
作者：
Akakura, Shin;Nochajski, Peter;Gelman, Irwin H.
AKAPs （A激酶锚定蛋白）的一个子集通过多种蛋白激酶（PKC和PKA）的时空支架调节信号传导和细胞骨架通路，并与质膜和基于肌动蛋白的细胞骨架相关联。SSeCKS/Gravin/Akap12在许多晚期癌症中表达严重下调，并表现出肿瘤和转移抑制活性。Akap12缺失（KO）小鼠发生局灶性不典型增生的前列腺增生，但Akap12阻止癌性进展的确切机制尚不清楚。在这里，我们发现KO小鼠胚胎成纤维细胞（MEF）表现出以多倍体和多核为特征的过早衰老，并且对致癌转化的易感性增加。尽管p53和Rb通路在缺乏Akap12的情况下被激活，但衰老依赖于Rb。衰老是由PKC α的激活驱动的，PKC α通过mek依赖性的Id1下调诱导p16(Ink4a)/Rb， PKC δ下调Lats1/Warts，这是细胞分裂所需的有丝分裂退出网络激酶。我们的数据强烈表明，Akap12通过直接支架和减弱PKC α / δ来控制rb介导的细胞衰老和致癌进展。
Asubset 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 PKC alpha, which induces p16(Ink4a)/Rb through a MEK-dependent downregulation of Id1, and PKC delta, 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 PKC alpha/delta.