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首页> 外文期刊>Cell cycle >Rb-dependent cellular senescence, multinucleation and susceptibility to oncogenic transformation through PKC scaffolding by SSeCKS/AKAP12.
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Rb-dependent cellular senescence, multinucleation and susceptibility to oncogenic transformation through PKC scaffolding by SSeCKS/AKAP12.

机译：通过SSeCKS / AKAP12通过PKC支架进行的Rb依赖性细胞衰老，多核化和对致癌转化的敏感性。

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摘要

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 PKCalpha, which induces p16(Ink4a)/Rb through a MEK-dependent downregulation of Id1, and PKCdelta, 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 PKCalpha/delta.
机译：AKAP（激酶锚定蛋白）的子集通过多种蛋白激酶（PK）（如PKC和PKA）的时空骨架以及与质膜和基于肌动蛋白的细胞骨架的关联来调节信号传导和细胞骨架途径。 SSeCKS / Gravin / Akap12表达在许多晚期癌症中严重下调，并表现出抑制肿瘤和转移的活性。 akap12 null（KO）小鼠发展为前列腺增生伴局灶性增生，但Akap12如何防止致癌进展的确切机制仍不清楚。在这里，我们显示KO小鼠胚胎成纤维细胞（MEF）表现出多倍体和多核化，并增加了对致癌转化的敏感性，标志着过早的衰老。尽管在没有Akap12的情况下激活了p53和Rb途径，但衰老取决于Rb。衰老是由PKCalpha的激活驱动的，PKCalpha的激活通过Id1的MEK依赖性下调诱导p16（Ink4a）/ Rb，而PKCdelta则下调Lats1 / Warts（胞质分裂所需的有丝分裂出口网络激酶）。我们的数据强烈表明Akap12通过直接脚手架和减弱PKCalpha /δ控制Rb介导的细胞衰老和致癌进程。

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