Mdm2 associates with Ras effector NORE1 to induce the degradation of oncoprotein HIPK1

Lee, Deresa; Park, Sang-Joon; Sung, Kyung Rim; Park, Jikyoung; Lee, Sean Bong; Park, Sang-Yoon; Lee, Hyo‐Jeong; Ahn, Ji Hyeon; Choi, So Jung; Lee, Seok‐Geun; Kim, Sung Hoon; Kim, Duk-Hwan; Kim, Young Tae; Kim, Yongsok; Choi, Cheol Yong

doi:10.1038/embor.2011.235

Cited by 28 publications

(24 citation statements)

References 9 publications

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“…Recent studies have shown that the ubiquitin ligase mdm2, a negative regulator of Rb that contributes to tumorigenesis in part by destabilizing Rb (67), can be found in an endogenous complex with PP1A (68), although the effects of mdm2 on PP1A stability have not been elucidated. Interestingly, NORE1A has been shown to regulate the degradation of specific mdm2 targets (69). Therefore, NORE1A could be regulating PP1A stability through its interaction with mdm2, potentially by antagonizing the ubiquitination/degradation properties of mdm2.…”

Section: Discussionmentioning

confidence: 99%

Ras Regulates Rb via NORE1A

Barnoud

Donninger²,

Clark

2016

Journal of Biological Chemistry

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Mutations in the Ras oncogene are one of the most frequent events in human cancer. Although Ras regulates numerous growth-promoting pathways to drive transformation, it can paradoxically promote an irreversible cell cycle arrest known as oncogene-induced senescence. Although senescence has clearly been implicated as a major defense mechanism against tumorigenesis, the mechanisms by which Ras can promote such a senescent phenotype remain poorly defined. We have shown recently that the Ras death effector NORE1A plays a critical role in promoting Ras-induced senescence and connects Ras to the regulation of the p53 tumor suppressor. We now show that NORE1A also connects Ras to the regulation of a second major prosenescent tumor suppressor, the retinoblastoma (Rb) protein. We show that Ras induces the formation of a complex between NORE1A and the phosphatase PP1A, promoting the activation of the Rb tumor suppressor by dephosphorylation. Furthermore, suppression of Rb reduces NORE1A senescence activity. These results, together with our previous findings, suggest that NORE1A acts as a critical tumor suppressor node, linking Ras to both the p53 and the Rb pathways to drive senescence.Ras mutations are the most frequent oncogenic events in human cancer and can be found in ϳ30% of all human cancers (1). In experimental systems, activated forms of Ras can be powerfully transforming, and transgenic animal models have validated the role of Ras activation in tumorigenesis (2, 3). However, despite the extensive evidence linking Ras to transformation and tumor development, activated Ras can also promote a state of irreversible cell cycle arrest called oncogeneinduced senescence (4, 5). This tendency for deregulated Ras activity to provoke senescence can be observed in Ras-driven tumors (6). It appears that senescence provides a potent barrier to suppress the development of Ras-driven cancer because malignant tumors lose the senescence phenotype (6). The exact mechanisms by which Ras can promote senescence are not completely understood, but it appears that the main Ras senescence pathways involve the p53 and retinoblastoma (Rb) 2 tumor suppressors (7). Initial evidence in mouse embryonic fibroblasts (MEFs) suggests that loss of functional p53 or Rb pathways alone is sufficient for Ras to bypass senescence (5). More recent studies have shown that, in vivo, suppression of p53 function (8) or Rb (9) enhances Ras-mediated transformation in murine systems. However, human systems may require inactivation of both p53 and Rb for full senescence evasion (10). Therefore, inactivation of the p53 and Rb senescence pathways may be essential for Ras-induced transformation.In addition to the classic trio of growth-promoting Ras effector proteins, Raf, PI3K, and RalGDS, Ras also interacts with growth-suppressing effector proteins, including NORE1A (RASSF5) (11,12). NORE1A is a member of the RASSF family of tumor suppressors that is frequently down-regulated during tumor development, and its inactivation has been linked to a rare familial cancer...

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Section: Discussionmentioning

confidence: 99%

Ras Regulates Rb via NORE1A

Barnoud

Donninger²,

Clark

2016

Journal of Biological Chemistry

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“…NORE1A forms a complex with MDM2, the principal regulator of p53 [43, 143] and regulates the stability of MDM2 in a Ras-dependent manner [144]. The mechanism appears to involve poly-ubiquitination mediated by the NORE1A/β-TrCP complex, in contrast to RASSF1A, which promotes MDM2 self-ubiquitination [44].…”

Section: Nore1a (Rassf5)mentioning

confidence: 99%

Ras signaling through RASSF proteins

Donninger

Schmidt

Mezzanotte

et al. 2016

Seminars in Cell & Developmental Biology

107

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There are six core RASSF family proteins that contain conserved Ras Association domains and may serve as Ras effectors. They lack intrinsic enzymatic activity and appear to function as scaffolding and localization molecules. While initially being associated with pro-apoptotic signaling pathways such as Bax and Hippo, it is now clear that they can also connect Ras to a surprisingly broad range of signaling pathways that control senescence, inflammation, autophagy, DNA repair, ubiquitination and protein acetylation. Moreover, they may be able to impact the activation status of pro-mitogenic Ras effector pathways, such as the Raf pathway. The frequent epigenetic inactivation of RASSF genes in human tumors disconnects Ras from pro-death signaling systems, enhancing Ras driven transformation and metastasis. The best characterized members are RASSF1A and RASSF5 (NORE1A).

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“…Required for apoptosis and growth inhibition [8] Inhibits MST2 activity [93] Modulates the MAP kinase signal downstream of the Ras signal [77] K-Ras [8] ST1, MST2 [177] MST1 [75] Not available 5A (Nore1A) 1q32 47.1 kDa Suppresses tumour growth via apoptosis induction or cell cycle delay [7,82] Regulates microtubule formation [182] Induces degradation of HIPK1 oncoprotein [183] Required for the TNFa mediated apoptosis and full activation of MST1 [80] Ras, Carma1 [182,184] MST1 [43,177] MST2 [177] tubulin, Aurora A [182] Mdm2 [183] Itch [185] Yes [80] resistant to TNFa-induced apoptosis, fail to activate Mst1 in vivo 5C (Nore1B, RAPL) 1q32 30.4 kDa…”

Section: Kdamentioning

confidence: 99%

RASSF tumor suppressor gene family: Biological functions and regulation

et al. 2014

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a b s t r a c tGenetic changes through allelic loss and nucleic acid or protein modifications are the main contributors to loss of function of tumor suppressor proteins. In particular, epigenetic silencing of genes by promoter hypermethylation is associated with increased tumor severity and poor survival. The RASSF (Ras association domain family) family of proteins consists of 10 members, many of which are tumor suppressor proteins that undergo loss of expression through promoter methylation in numerous types of cancers such as leukemia, melanoma, breast, prostate, neck, lung, brain, colorectal and kidney cancers. In addition to their tumor suppressor function, RASSF proteins act as scaffolding agents in microtubule stability, regulate mitotic cell division, modulate apoptosis, control cell migration and cell adhesion, and modulate NFjB activity and the duration of inflammation. The ubiquitous functions of these proteins highlight their importance in numerous physiological pathways. In this review, we will focus on the biological roles of the RASSF family members and their regulation.

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Mdm2 associates with Ras effector NORE1 to induce the degradation of oncoprotein HIPK1

Cited by 28 publications

References 9 publications

Ras Regulates Rb via NORE1A

Ras Regulates Rb via NORE1A

Ras signaling through RASSF proteins

RASSF tumor suppressor gene family: Biological functions and regulation

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