The RasGAP Gene, RASAL2, Is a Tumor and Metastasis Suppressor

McLaughlin, Sara Koenig; Olsen, Sarah Naomi; Dake, Benjamin T.; Raedt, Thomas De; Lim, Elgene; Bronson, Roderick T.; Beroukhim, Rameen; Polyák, Kornélia; Brown, Myles; Kuperwasser, Charlotte; Cichowski, Karen

doi:10.1016/j.ccr.2013.08.004

Cited by 114 publications

(140 citation statements)

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“…EMT in mammary epithelial cells typically facilitates tumor cell migration and invasion (27). Previously, RASAL2 was identified as a mediator of EMT and metastasis in ovarian cancer, lung adenocarcinoma and breast cancer (14)(15)(16). In the present study, RASAL2 was demonstrated to be a mediator of EMT, migration and invasion in CRC cells.…”

Section: Discussionmentioning

confidence: 58%

“…Mutations in RAS genes frequently lead to permanently activated RAS and thus its downstream effectors, which causes aberrant cell proliferation and potential tumorigenesis (14). Previous studies have demonstrated that mutation of RAS genes is the primary mechanism of aberrant RAS activation (8,20,21).…”

Section: Discussionmentioning

confidence: 99%

“…RASAL2 was reported to be mutated or suppressed in RAS-and ERK-hyperactivated breast cancer, where RASAL2 downregulation promoted tumor growth, progression and metastasis in two distinct human xenograft tumor models (14). Silencing of the RAS-GAPs RASAL1, DAB2 interacting protein (DAB2IP) and neurofibromin 1 leads to aberrant RAS activation in HCC cells (23).…”

Section: Discussionmentioning

confidence: 99%

“…RASAL2 expression is suppressed by hypermethylation of its promoter, which leads to Ras signaling, and subsequent tumor growth and metastasis in human breast cancer (12,13). Decreased RASAL2 expression is correlated with metastasis, recurrence and poor disease outcome in luminal B tumors (14). However, RASAL2 is upregulated in a subset of triple-negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumors, and is a direct target of microRNA 203, which has anti-invasive functions (13).…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of RASAL2 promotes the proliferation, epithelial-mesenchymal transition and metastasis of colorectal cancer cells

et al. 2017

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Abstract. RAS protein activator like 2 (RASAL2) is a RAS-GTPase-activating protein and has recently been identified to be a tumor suppressor in various types of human cancer; however, the function of RASAL2 in colorectal carcinoma (CRC) remains unclear. In the present study, the function of RASAL2 in CRC cells was investigated using a RASAL2 loss-of-function cell model. RASAL2 short hairpin RNA was transfected into the human CRC cell lines LoVo, SW620 and HCT116, and the wild-type colon cell line NCM460. The subsequent downregulation of RASAL2 was evaluated using western blot and reverse transcription-quantitative polymerase chain reaction analyses. It was observed that RASAL2 expression was significantly decreased in human CRC tissues and cell lines (P<0.01). In the loss-of-function cell models, RASAL2 expression was decreased significantly, while cell proliferation, colony formation, migration and invasion were increased (all P<0.01). These effects were associated with the induction of epithelial-mesenchymal transition and Raf/mitogen-activated protein kinase hyperactivation. The results of the present study indicate that RASAL2 is a potential therapeutic target to inhibit CRC progression and metastasis.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Downregulation of RASAL2 promotes the proliferation, epithelial-mesenchymal transition and metastasis of colorectal cancer cells

et al. 2017

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“…45 RASAL2, a closely related member in the RASAL1 family, has also been shown to suppress tumorigenicity and metastasis. 46 This general characteristic of RASAL genes needs further investigation to obtain confirmation.…”

Section: Discussionmentioning

confidence: 99%

Chromosome 12 long arm rearrangement covering MDM2 and RASAL1 is associated with aggressive craniofacial juvenile ossifying fibroma and extracranial psammomatoid fibro-osseous lesions

et al. 2015

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To evaluate the diagnostic value of MDM2 status in craniofacial fibro-osseous lesions, we investigated MDM2 expression by immunohistochemistry and analyzed MDM2 amplification by qPCR in 30 cases of ossifying fibroma (including 13 cases of the juvenile variant) and 17 cases of fibrous dysplasia. Two cases of uncommon extragnathic psammomatoid fibrous dysplasia and a mixed control group of 15 cases of low-grade osteosarcoma and 15 cases of well-differentiated/dedifferentiated liposarcoma were included. MDM2 amplification was found in 33% of ossifying fibromas (peak of 69% for the juvenile variant) and in 12% of fibrous dysplasia, in none of which was MDM2 overexpressed. All control cases exhibited MDM2 amplification and overexpression. To investigate possible polysomy of chromosome 12, we studied RASAL1 amplification, a gene telomeric to MDM2 on the long arm of chromosome 12. RASAL1 amplification was reported in all benign fibro-osseous lesions exhibiting MDM2 amplification but not in controls. Simultaneous amplification of these two genes was significantly higher in juvenile ossifying fibromas compared with fibrous dysplasia (P ¼ 0.004), non-juvenile ossifying fibromas (P ¼ 0.001), and all other benign craniofacial fibro-osseous lesions combined (P ¼ 0.0001). Of the nine cases of juvenile ossifying fibroma exhibiting amplification, three were locally invasive and four were recurrent, suggesting aggressive disease. The two cases of extragnathic psammomatoid fibrous dysplasia also showed MDM2 and RASAL1 amplification with no MDM2 overexpression. This large chromosome 12 rearrangement, spanning MDM2 and RASAL1, is the first recurrent molecular abnormality to be reported in juvenile ossifying fibroma. It may represent both a molecular diagnostic marker and a characteristic of more aggressive forms with a higher risk of recurrence. Finally, the presence of this rearrangement in extragnathic psammomatoid fibro-osseous lesions mimicking ossifying fibromas might reflect a common molecular pathway in their pathogenesis and calls into question the classification of such lesions within fibrous dysplasia.

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RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells

et al. 2015

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Ras GTPase-activating proteins negatively regulate the Ras/Erk signaling pathway, thereby playing crucial roles in the proliferation, function, and development of various types of cells. In this study, we identified a novel Ras GTPase-activating proteins protein, RASAL3, which is predominantly expressed in cells of hematopoietic lineages, including NKT, B, and T cells. We established systemic RASAL3-deficient mice, and the mice exhibited a severe decrease in NKT cells in the liver at 8 weeks of age. The treatment of RASAL3-deficient mice with α-GalCer, a specific agonist for NKT cells, induced liver damage, but the level was less severe than that in RASAL3-competent mice, and the attenuated liver damage was accompanied by a reduced production of interleukin-4 and interferon-γ from NKT cells. RASAL3-deficient NKT cells treated with α-GalCer in vitro presented augmented Erk phosphorylation, suggesting that there is dysregulated Ras signaling in the NKT cells of RASAL3-deficient mice. Taken together, these results suggest that RASAL3 plays an important role in the expansion and functions of NKT cells in the liver by negatively regulating Ras/Erk signaling, and might be a therapeutic target for NKT-associated diseases.Keywords: α-GalCer r IL-4 r Liver injury r NKT cell r Ras r RasGAP Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionRas proteins have been shown to play pivotal roles in proliferation, differentiation, and oncogenesis by functioning as a molecular switch for intracellular signaling pathways [1,2]. In order to act as a switch, Ras has two forms, an inactive GDP-bound form and an active GTP-bound form. GDP-bound Ras is dominant under the steady-state condition. Upon agonist binding to its receptor on the cell membrane, GDP-bound Ras is converted into active GTPbound Ras, which stimulates downstream signaling cascades, such as the Raf/Erk and phosphoinositide-3 kinase/Akt pathways [3]. Such switching of Ras forms is controlled by its intrinsic GTPase activity, and a balance between Ras guanine nucleotide exchange factors (RasGEFs) and Ras GTPase-activating proteins (RasGAPs) [4]. While RasGEFs act as a positive factor for Ras signaling by stimulating the conversion of Ras-GDP into Ras-GTP, RasGAPs act as negative factors by stimulating the rate of GTP hydrolysis from Ras-GTP into Ras-GDP [4]. Ras regulates the activation, differentiation, and proliferation of lymphoid cells. For instance, p21ras (K-Ras) regulates the function and growth of T cells and thymocytes during both immune activation and T-cell development [5][6][7]. In addition, TCR activation in T cells stimulates Ras, which initiates downstream signaling pathways leading to the production of cytokines such as IL-2, and subsequent IL-2-induced proliferation [8,9]. A deficiency of the RasGRP1 gene, a RasGEF, in mice inactivates the TCR activation-induced Ras signaling in thymocytes, and the mice have reduced single-positive (CD4 + CD8 − and CD4 − CD8 + ) thymocytes [10]....

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The RasGAP Gene, RASAL2, Is a Tumor and Metastasis Suppressor

Cited by 114 publications

References 43 publications

Downregulation of RASAL2 promotes the proliferation, epithelial-mesenchymal transition and metastasis of colorectal cancer cells

Downregulation of RASAL2 promotes the proliferation, epithelial-mesenchymal transition and metastasis of colorectal cancer cells

Chromosome 12 long arm rearrangement covering MDM2 and RASAL1 is associated with aggressive craniofacial juvenile ossifying fibroma and extracranial psammomatoid fibro-osseous lesions

RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells

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