Nuclear Transport of Ras-associated Tumor Suppressor Proteins: Different Transport Receptor Binding Specificities for Arginine-rich Nuclear Targeting Signals

Kumari, Gita; Singhal, Prabhat K.; Rao, Meera; Mahalingam, Sundarasamy

doi:10.1016/j.jmb.2007.01.026

Cited by 34 publications

(41 citation statements)

References 53 publications

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“…COS-7 cells were transfected with RFP-RASSF2 and GFP-PAR-4 and then analyzed by fluorescence microscopy for subcellular localization of the proteins in live cells. Consistent with previous studies, when transfected alone RASSF2 was localized in the nucleus (7,29,47), whereas PAR-4 was located predominantly in the cytoplasm and on the cell membrane (Fig. 3A).…”

Section: Rassf2 Interacts Directly With Par-4supporting

confidence: 92%

“…We have previously shown that, unlike RASSF1A, RASSF2 localizes primarily to the nucleus (7,47). PAR-4 requires nuclear localization for its apoptotic functions (15,23), and it has been suggested that RASSF2 has the potential to serve as part of a nuclear transport system (29). Thus, we examined the effects of RASSF2 on the nuclear localization of PAR-4.…”

Section: Rassf2 Interacts Directly With Par-4mentioning

confidence: 98%

“…However, the mechanism by which RASSF2 promotes cell death and tumor inhibition is completely unknown. It seems likely that it may differ from the mechanisms employed by RASSF1A, a primarily cytoplasmic protein, as RASSF2 localizes mostly to the nucleus (7,29). As with RASSF1A, RASSF2 has no apparent intrinsic enzyme activity or DNA binding properties, and thus it may interact with other proapoptotic effectors/tumor suppressors to medi-ate cell death.…”

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confidence: 99%

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The Ras Effector RASSF2 Controls the PAR-4 Tumor Suppressor

Donninger

Hesson

Vos³

et al. 2010

Molecular and Cellular Biology

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RASSF2 is a novel proapoptotic effector of K-Ras. Inhibition of RASSF2 expression enhances the transforming effects of K-Ras, and epigenetic inactivation of RASSF2 is frequently detected in mutant Rascontaining primary tumors. Thus, RASSF2 is implicated as a tumor suppressor whose inactivation facilitates transformation by disconnecting apoptotic responses from Ras. The mechanism of action of RASSF2 is not known. Here we show that RASSF2 forms a direct and endogenous complex with the prostate apoptosis response protein 4 (PAR-4) tumor suppressor. This interaction is regulated by K-Ras and is essential for the full apoptotic effects of PAR-4. RASSF2 is primarily a nuclear protein, and shuttling of PAR-4 from the cytoplasm to the nucleus is essential for its function. We show that RASSF2 modulates the nuclear translocation of PAR-4 in prostate tumor cells, providing a mechanism for its biological effects. Thus, we identify the first tumor suppressor signaling pathway emanating from RASSF2, we identify a novel mode of action of a RASSF protein, and we provide an explanation for the extraordinarily high frequency of RASSF2 inactivation we have observed in primary prostate tumors.

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Section: Rassf2 Interacts Directly With Par-4supporting

confidence: 92%

Section: Rassf2 Interacts Directly With Par-4mentioning

confidence: 98%

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confidence: 99%

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The Ras Effector RASSF2 Controls the PAR-4 Tumor Suppressor

Donninger

Hesson

Vos³

et al. 2010

Molecular and Cellular Biology

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“…The RASSF2 gene has been shown to be frequently inactivated by promoter methylation in a wide range of tumor types, including colorectal, gastric, oral, nasopharyngeal, breast and lung cancers (12)(13)(14)(15)(16). Further studies have identified that RASSF2 has a putative nuclear localization signal (NLS) and a nuclear export signal (NES) at the N-and C-terminal regions, respectively (17). In addition, RASSF2 acts in a complex manner that extends beyond simple protein-protein association to play an important role in MST1 regulation as RASSF2 protein stability is significantly decreased in the absence of MST1 in vitro and in vivo (18).…”

Section: Introductionmentioning

confidence: 99%

Ectopic expression of RASSF2 and its prognostic role for gastric adenocarcinoma patients

Luo

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. RASSF2 has recently been identified as a potential tumor suppressor that serves as a Ras effector in various types of human cancers. However, there have been few reports detailing this in gastric cancer. Samples of gastric adenocarcinoma from 276 Chinese patients with follow-up were analyzed for RASSF2 protein expression by immunohistochemistry. RASSF2 was expressed in up to 31.2% (86/276) of this group of gastric carcinoma. The expression of RASSF2 was significantly lower in carcinomas than in normal mucosas (P<0.05). RASSF2 corresponded positively with patient age, histological differentiation, depth of tumor invasion, regional lymph node and distant metastasis, and TNM stage (all P<0.05). Further multivariate analysis revealed that patient gender, depth of tumor invasion, distant metastasis, TNM stage and the expression of RASSF2 were independent prognostic factors for patients with gastric cancer. The Kaplan-Meier plot showed that the overall mean survival time of the patients with RASSF2-negative expression was shorter than that of patients with positive expression (χ 2 =156.874, P<0.0001). Moreover, RASSF2-negative expression had a much more significant effect on the survival of those patients with early stage tumors (χ 2 =127.167, P<0.0001), highlighted by a >50.9% reduction in 3-year survival compared to that of patients with RASSF2-positive expression. In late stages, the difference was also significant (χ 2 =6.246, P= 0.019), with a 35.5% reduction in 3-year survival. It is suggested that RASSF2 plays an important role in the evolution of gastric adenocarcinoma and should be considered as a potential marker for its prognosis.

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“…One study also reports that NORE1A appears to shuttle between the nucleus and the cytoplasm, although it is primarily detected in small spots in the nucleus [246]. PML is a protein that is well known for forming large nuclear aggregates of various proteins, the major component of which is PML, hence the term, PML 68!…”

Section: Nore1a Co-localizes With Pmlivmentioning

confidence: 99%

The discovery of a novel, Ras-mediated NORE1A/PMLIV tumor suppressor complex.

Sharpe¹

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Nuclear Transport of Ras-associated Tumor Suppressor Proteins: Different Transport Receptor Binding Specificities for Arginine-rich Nuclear Targeting Signals

Cited by 34 publications

References 53 publications

The Ras Effector RASSF2 Controls the PAR-4 Tumor Suppressor

The Ras Effector RASSF2 Controls the PAR-4 Tumor Suppressor

Ectopic expression of RASSF2 and its prognostic role for gastric adenocarcinoma patients

The discovery of a novel, Ras-mediated NORE1A/PMLIV tumor suppressor complex.

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