Identification of Ras-Related Nuclear Protein, Targeting Protein for <i>Xenopus</i> Kinesin-like Protein 2, and Stearoyl-CoA Desaturase 1 as Promising Cancer Targets from an RNAi-Based Screen

Morgan-Lappe, Susan E.; Tucker, Lora; Huang, Xiaoli; Zhang, Qian; Sarthy, Aparna V.; Zakula, Dorothy; Vernetti, Lawrence; Schurdak, Mark E.; Wang, Jieyi; Fesik, Stephen W.

doi:10.1158/0008-5472.can-06-4132

Cited by 126 publications

(107 citation statements)

References 50 publications

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“…Ran was also shown to be highly expressed in gastric, colon, pancreatic, and lung cancer tissues, but not in normal cells within the same tumor sample (39). Additionally, in an RNA interference-based screen, the knockdown of Ran and a protein under Ran regulation in mitotic spindle assembly, TPX2, was found to significantly reduce the survival of multiple human tumor cell lines (40). More recently, it was shown that the overexpression of wild type Ran was sufficient to transform rat mammary cells (34).…”

Section: Discussionmentioning

confidence: 99%

Activation of the Ran GTPase Is Subject to Growth Factor Regulation and Can Give Rise to Cellular Transformation

Wang

Pereira

et al. 2010

Journal of Biological Chemistry

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Although the small GTPase Ran is best known for its roles in nucleocytoplasmic transport, mitotic spindle assembly, and nuclear envelope formation, recent studies have demonstrated the overexpression of Ran in multiple tumor types and that its expression is correlated with a poor patient prognosis, providing evidence for the importance of this GTPase in cell growth regulation. Here we show that Ran is subject to growth factor regulation by demonstrating that it is activated in a serum-dependent manner in human breast cancer cells and, in particular, in response to heregulin, a growth factor that activates the Neu/ ErbB2 tyrosine kinase. The heregulin-dependent activation of Ran requires mTOR (mammalian target of rapamycin) and stimulates the capped RNA binding capability of the cap-binding complex in the nucleus, thus influencing gene expression at the level of mRNA processing. We further demonstrate that the excessive activation of Ran has important consequences for cell growth by showing that a novel, activated Ran mutant is sufficient to transform NIH-3T3 cells in an mTOR-and epidermal growth factor receptor-dependent manner and that Ran-transformed cells form tumors in mice.Ran is a unique member of the Ras superfamily of GTPases that utilizes a guanine nucleotide exchange factor (the chromatin-associated RCC1 protein), a GTPase-accelerating protein complex (RanGAP/RanBP1), and a single major class of effectors (the importins or karyopherins) to regulate the nucleocytoplasmic transport of various cargo as well as other nuclear functions (for review, see Ref. 1). In interphase cells, a Ran-GTP gradient is formed in response to the nuclear localization of RCC1 together with the cytoplasmic localization of RanGAP. As a result, Ran exists predominantly in an active, GTP-bound state in the nucleus where it is capable of engaging its primary biological effectors, the importins/karyopherins. GTP hydrolysis, catalyzed by RanGAP in the cytoplasm, then results in the dissociation of Ran-GDP from its effector proteins. The nucleocytoplasmic transport of a number of proteins is dependent upon the proper establishment of the Ran-GTP gradient, as best exemplified in the case of classical nuclear import (2). Protein cargo destined for the nucleus is identified by the presence of a nuclear localization sequence. The nuclear localization sequence is recognized by an adapter protein, importin-␣, in the cytosol, and upon binding the cargo, importin-␣ engages importin-␤ to form a complete import complex that translocates to the nucleus. Within the nucleus, Ran-GTP binds to importin-␤, causing it to dissociate from the import complex, which results in the subsequent release of cargo. Thus, the fact that Ran-GTP is predominantly a nuclear species is pivotal in the directional release of import cargo into the nucleus.Similarly, it has been suggested that Ran plays an essential role in the directional release of capped RNAs in the cytoplasm by regulating the interactions that occur between the nuclear cap-binding complex (CBC) 2 ...

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Section: Discussionmentioning

confidence: 99%

Activation of the Ran GTPase Is Subject to Growth Factor Regulation and Can Give Rise to Cellular Transformation

Wang

Pereira

et al. 2010

Journal of Biological Chemistry

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“…First, both Aurora A and TPX2 (initially identified as REPP86 (restrictedly expressed proliferation-associated protein of 86 kDa) are overexpressed in some tumors (61)(62)(63). Furthermore, knockdown of TPX2 significantly reduces the survival of multiple human cancer cell lines (64). Second, pharmacological inhibitors targeting the oncogenic kinase Aurora A also target Aurora B in most cases.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of p53 Is Regulated by TPX2-Aurora A in Xenopus Oocytes

Pascreau

Eckerdt

Lewellyn

et al. 2009

Journal of Biological Chemistry

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p53 is an important tumor suppressor regulating the cell cycle at multiple stages in higher vertebrates. The p53 gene is frequently deleted or mutated in human cancers, resulting in loss of p53 activity. This leads to centrosome amplification, aneuploidy, and tumorigenesis, three phenotypes also observed after overexpression of the oncogenic kinase Aurora A. Accordingly, recent studies have focused on the relationship between these two proteins. p53 and Aurora A have been reported to interact in mammalian cells, but the function of this interaction remains unclear. We recently reported that Xenopus p53 can inhibit Aurora A activity in vitro but only in the absence of TPX2. Here we investigate the interplay between Xenopus Aurora A, TPX2, and p53 and show that newly synthesized TPX2 is required for nearly all Aurora A activation and for full p53 synthesis and phosphorylation in vivo during oocyte maturation. In vitro, phosphorylation mediated by Aurora A targets serines 129 and 190 within the DNA binding domain of p53. Glutathione S-transferase pull-down studies indicate that the interaction occurs via the p53 transactivation domain and the Aurora A catalytic domain around the T-loop. Our studies suggest that targeting of TPX2 might be an effective strategy for specifically inhibiting the phosphorylation of Aurora A substrates, including p53.

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“…38 SCD1 knockdown resulted in 40% cell survival in the human non-small cell lung carcinoma cell line (H1299), 75% survival in human colon cancer cells, whereas human breast carcinoma cell line MDA-MB-468 seemed unaffected. 38 The decrease in cell survival through apoptosis was thought to be mediated via upregulation of Caspase 3.…”

Section: Role Of Scd1 In the Link Between Obesity And Cancermentioning

confidence: 99%

“…In addition, SCD expression may be changed during the development of cancer. 22,38 Interestingly, SCD1 mRNA and protein upregulation correlates with neural regeneration in rat. 39 Also, in human SCD1 and especially SCD2 mRNA is highly upregulated human fetal brain, suggesting a role for SCD in human brain development.…”

Section: Introductionmentioning

confidence: 99%

Role of stearoyl-CoA desaturases in obesity and the metabolic syndrome

2008

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The prevalence of obesity and related metabolic disorders increases rapidly in western societies. A proper choice of foods may now prevent or delay many of the health consequences related to these disorders. In this respect, replacing dietary saturated fatty acids (SFAs) by cis-monounsaturated fatty acids (cis-MUFAs) has beneficial effects. In addition to diet-derived cis-MUFAs, the human body can also generate cis-MUFAsfrom SFAs through the action of stearoyl-CoA desaturases (SCDs). SCDs may play an adverse role in obesity and obesity-related insulin resistance. Here, we review the current knowledge on the molecular aspects and the role of SCD1 in obesity and the metabolic syndrome (MS). In mice, many studies have suggested a negative role for SCD1 in the development of obesity and insulin resistance. In humans, however, evidence is less convincing. If anything, increased, rather than decreased, levels of SCD1 mRNA levels are negatively associated with MS-related diseases such as insulin resistance. However, an unequivocal conclusion is currently not possible as the number of human studies is limited. Therefore, more human studies are needed at the molecular as well as at the physiological level to understand the true role of SCD1 during the development of obesity and the MS.

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Identification of Ras-Related Nuclear Protein, Targeting Protein for Xenopus Kinesin-like Protein 2, and Stearoyl-CoA Desaturase 1 as Promising Cancer Targets from an RNAi-Based Screen

Cited by 126 publications

References 50 publications

Activation of the Ran GTPase Is Subject to Growth Factor Regulation and Can Give Rise to Cellular Transformation

Activation of the Ran GTPase Is Subject to Growth Factor Regulation and Can Give Rise to Cellular Transformation

Phosphorylation of p53 Is Regulated by TPX2-Aurora A in Xenopus Oocytes

Role of stearoyl-CoA desaturases in obesity and the metabolic syndrome

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