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Growth and tumor suppressor NORE1A is a regulatory node between Ras signaling and microtubule nucleation.

ABSTRACT: NORE1A is a Ras-binding protein that belongs to a group of tumor suppressors known as the Ras association domain family. Their growth- and tumor-suppressive function is assumed to be dependent on association with the microtubule cytoskeleton. However, a detailed understanding of this interplay is still missing. Here, we show that NORE1A directly interacts with tubulin and is capable of nucleating microtubules. Strikingly, the ability to stimulate nucleation is regulated in a dual specific way either via phosphorylation of NORE1A within the Ras-binding domain by Aurora A kinase or via binding to activated Ras. We also demonstrate that NORE1A mediates a negative effect of activated Ras on microtubule nucleation. On the basis of our results, we propose a novel regulatory network composed of the tumor suppressor NORE1A, the mitotic kinase Aurora A, the small GTPase Ras, and the microtubule cytoskeleton.

SUBMITTER: Bee C

PROVIDER: S-EPMC2871493 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Growth and tumor suppressor NORE1A is a regulatory node between Ras signaling and microtubule nucleation.

Bee Christine C Moshnikova Anna A Mellor Christopher D CD Molloy Justin E JE Koryakina Yulia Y Stieglitz Benjamin B Khokhlatchev Andrei A Herrmann Christian C

The Journal of biological chemistry 20100325 21

NORE1A is a Ras-binding protein that belongs to a group of tumor suppressors known as the Ras association domain family. Their growth- and tumor-suppressive function is assumed to be dependent on association with the microtubule cytoskeleton. However, a detailed understanding of this interplay is still missing. Here, we show that NORE1A directly interacts with tubulin and is capable of nucleating microtubules. Strikingly, the ability to stimulate nucleation is regulated in a dual specific way ei ...[more]

PMID: 20339001

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Project description:Simple Summary The loss of function of the BRCA1 tumor suppressor is common in breast cancer, but experimentally, the BRCA1 inactivation promotes cell senescence. The overstimulation of RAS signaling via Her2 upregulation is also common in breast cancer, yet it can also lead to senescence. A significant percent of primary breast tumors exhibit both defects. So how do they overcome the senescence response to become successful tumors? Here we show that the RAS senescence effector NORE1A can complex with BRCA1 and that loss of NORE1A abrogates the senescence-inducing effects of Her2 and BRCA1 dysregulation. Database analysis shows that NORE1A loss of expression is common in primary breast tumors and correlates with BRCA1 loss in Her2+ but not Her2− cases. Abstract BRCA1 is a tumor suppressor with a complex mode of action. Hereditary mutations in BRCA1 predispose carriers to breast cancer, and spontaneous breast cancers often exhibit defects in BRCA1 expression. However, haploinsufficiency or suppression of BRCA1 expression leads to defects in DNA repair, which can induce DNA damage responses, leading to senescence. Activating mutation or overexpression of the Her2 oncoprotein are also frequent drivers of breast cancer. Yet, over-activation of Her2, working through the RAS oncoprotein, can also induce senescence. It is thought that additional defects in the p53 and Rb tumor suppressor machinery must occur in such tumors to allow an escape from senescence, thus permitting tumor development. Although BRCA1 mutant breast cancers are usually Her2 negative, a significant percentage of Her2 positive tumors also lose their expression of BRCA1. Such Her2+/BRCA1− tumors might be expected to have a particularly high senescence barrier to overcome. An important RAS senescence effector is the protein NORE1A, which can modulate both p53 and Rb. It is an essential senescence effector of the RAS oncoprotein, and it is often downregulated in breast tumors by promotor methylation. Here we show that NORE1A forms a Her2/RAS regulated, endogenous complex with BRCA1 at sites of replication fork arrest. Suppression of NORE1A blocks senescence induction caused by BRCA1 inactivation and Her2 activation. Thus, NORE1A forms a tumor suppressor complex with BRCA1. Its frequent epigenetic inactivation may facilitate the transformation of Her2+/BRCA1− mediated breast cancer by suppressing senescence.

Dataset Information

Growth and tumor suppressor NORE1A is a regulatory node between Ras signaling and microtubule nucleation.

Publications

Growth and tumor suppressor NORE1A is a regulatory node between Ras signaling and microtubule nucleation.

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