Dataset Information

Phosphorylation-regulated degradation of the tumor-suppressor form of PED by chaperone-mediated autophagy in lung cancer cells.

ABSTRACT: PED/PEA-15 is a death effector domain (DED) family member with a variety of effects on cell growth and metabolism. To get further insight into the role of PED in cancer, we aimed to find new PED interactors. Using tandem affinity purification, we identified HSC70 (Heat Shock Cognate Protein of 70?kDa)-which, among other processes, is involved in chaperone-mediated autophagy (CMA)-as a PED-interacting protein. We found that PED has two CMA-like motifs (i.e., KFERQ), one of which is located within a phosphorylation site, and demonstrate that PED is a bona fide CMA substrate and the first example in which phosphorylation modifies the ability of HSC70 to access KFERQ-like motifs and target the protein for lysosomal degradation. Phosphorylation of PED switches its function from tumor suppression to tumor promotion, and we show that HSC70 preferentially targets the unphosphorylated form of PED to CMA. Therefore, we propose that the up-regulated CMA activity characteristic of most types of cancer cell enhances oncogenesis by shifting the balance of PED function toward tumor promotion. This mechanism is consistent with the notion of a therapeutic potential for targeting CMA in cancer, as inhibition of this autophagic pathway may help restore a physiological ratio of PED forms.

SUBMITTER: Quintavalle C

PROVIDER: S-EPMC4310550 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phosphorylation-regulated degradation of the tumor-suppressor form of PED by chaperone-mediated autophagy in lung cancer cells.

Quintavalle Cristina C Di Costanzo Stefania S Zanca Ciro C Tasset Immaculada I Fraldi Alessandro A Incoronato Mariarosaria M Mirabelli Peppino P Monti Maria M Ballabio Andrea A Pucci Piero P Cuervo Ana Maria AM Condorelli Gerolama G

Journal of cellular physiology 20141001 10

PED/PEA-15 is a death effector domain (DED) family member with a variety of effects on cell growth and metabolism. To get further insight into the role of PED in cancer, we aimed to find new PED interactors. Using tandem affinity purification, we identified HSC70 (Heat Shock Cognate Protein of 70 kDa)-which, among other processes, is involved in chaperone-mediated autophagy (CMA)-as a PED-interacting protein. We found that PED has two CMA-like motifs (i.e., KFERQ), one of which is located within ...[more]

PMID: 24477641

Similar Datasets

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

Phosphorylation-regulated degradation of the tumor-suppressor form of PED by chaperone-mediated autophagy in lung cancer cells.

Publications

Phosphorylation-regulated degradation of the tumor-suppressor form of PED by chaperone-mediated autophagy in lung cancer cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets