RasGRP Ras guanine nucleotide exchange factors in cancer

Ksionda, Olga; Limnander, André; Roose, Jeroen P.

doi:10.1007/s11515-013-1276-9

Cited by 51 publications

(82 citation statements)

References 161 publications

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“…50 Proteins involved in cell proliferation were also found, including GSG2, a kinase responsible for mitotic histone production 51 and guanine nucleotide exchange factor RASGRF1, which is responsible for cell proliferation and migration related to metastatic in tumorogenesis. 52 However, this tissue also showed the presence of tumor suppressor CHD1. 53 Decreased level β-actin in primary tumor in response to possible cytoskeleton dynamic modification…”

Section: Resultsmentioning

confidence: 89%

Morpho/Proteomic Comparative between High Grade Pleomorphic Sarcoma and Metastasis Diagnosed in an Old Captive Common Hippo

Silva¹,

Lacerda²,

Faria³

et al. 2017

J. Braz. Chem. Soc.

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Old age is a risk factor for cancer development in humans and animals, and studies have shown that tumors in animals are acceptable models for studying human cancers, considering the similarities between their factors. This work was conducted in a 53-year-old captive female common hippo (Hippopotamus amphibious) with a left leg tumor and metastatic mass. Histopathological and immunohistochemical analyses were carried out with a final diagnosis of a high grade pleomorphic sarcoma. A proteomic study using mass spectrometry was added in order to identify further aspects of the primary tumor and metastasis which could improve our understanding, and each tissue showed a proteomic profile indicative of its pathologic state with significant differences between healthy tissue, primary and metastatic tumors. Low levels of β-actin in primary tumors were identified, and this may be associated with a possible consequence of cytoskeleton dynamic modification. In metastatic tissue, these dynamics may be affected by the presence of HSP chaperone 60. Keywords:Hippopotamus amphibious, high grade pleomorphic sarcoma, cytoskeleton, β-actin, mass spectrometry IntroductionOncogenic phenomena in animals include a wide variety of benign and malignant tumors that develop during the life of the animal and have several health consequences. 1 Species with large bodies tend to have a lower cancer rate, which seems to indicate the presence of complex tumor detection systems (Peto's paradox).2 To illustrate this paradox, in contrast with humans, who have only two copies of the TP53 tumor suppressor gene, elephants, the largest of the land mammmals, have 20 copies of the TP53 gene. This allows for extra efficiency in their systems, enabling the correction of DNA damage or inducing apoptosis in mutated cells. As a result, only 3% of elephants develop cancer. 3,4 Despite some comparative cancer and lifespan analyses between wild and zoo animals showing that captive animals were susceptible to cancer and decreased longevity. 5,6 Tidière et al. 7 revealed that mammals from zoo populations generally lived longer than their wild counterparts (84% of species). Of particular interest, the common hippopotamus (Hippopotamus amphibius), a robust mammal with an estimated 40-year lifespan in nature and with slow pace of life, has increased longevity in captivity. [7][8][9] The relationship between life expectancy and environment may be associated with the low caloric diet and reduced metabolism present in captive animals, which slows ageing and the appearance of cancer cases. This is also true for humans. 10,11 Paradoxically, the exceptional longevity these captive animals exhibit can be associated with cancer due to several factors such as telomere shortening, increased cellular senescence, accumulation mutation of DNA in stem and progenitor cells required for active replenishment during the lifespan of the organism, mutations in tumor suppressor genes and metabolic changes. 12-14Based on available database information and proteomics approach, it is poss...

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Section: Resultsmentioning

confidence: 89%

Morpho/Proteomic Comparative between High Grade Pleomorphic Sarcoma and Metastasis Diagnosed in an Old Captive Common Hippo

Silva¹,

Lacerda²,

Faria³

et al. 2017

J. Braz. Chem. Soc.

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“…19,20 Rasgrp1-deficient mice have a severe T cell development defect in the thymus 21 whereas Rasgrp3-deficient mice show subtle defects in B cell development. 22 RasGRP4 has been show to play an important role in mast cells and neutrophils functions.…”

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confidence: 99%

“…22 RasGRP4 has been show to play an important role in mast cells and neutrophils functions. 20 The default path to inactivate Ras prevails in normal cells via the intrinsic, selfinactivating GTPase function of Ras. This function is enhanced by the action of RasGAPs (Ras GTPase activating protein).…”

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confidence: 99%

“…[25][26][27] In addition to lesions in Ras itself, mutations can occur in genes encoding upstream receptors or in other pathway constituents, chromosomal translocations can have deregulating activities, and alterations in expression levels of key components can have major impacts on the activity through the Ras pathway. 20,28 Recent studies have started to map out the pathways that can lead to aberrant Ras signals in T-ALL. Whole genome sequencing revealed activating mutations in the cytokine receptor IL7R (Interleukin 7 receptor) and in JAK1 and JAK3 (Janus kinase 1 and 3), 1 and the IL7R mutations found in T-ALL constitutively activate downstream JAK1 kinase.…”

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confidence: 99%

“…29 Studies with different mouse models and with pediatric T-ALL patient samples pointed to a role for RasGRP1 in T-ALL leukemogenesis. 20,[30][31][32][33] Likewise, the inactivating function of RasGAPs on the Ras pathway also appears critical; combined T cell-specific deletion of NF1 and p120 RasGAPs in mice leads to development of T-ALL 34 and NF1 is mutated in both pediatric and adult T-ALL patients. [35][36][37] In our recent study by Ksionda et al 38 we describe the details of cytokine receptor-Ras pathways in T-ALL and how Ras signals in T-ALL with RasGRP1 overexpression not only differ from those in developing normal T cells (thymocytes) but also from Ras signals in Ras MUT T-ALL.…”

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confidence: 99%

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Distinct oncogenic Ras signals characterized by profound differences in flux through the RasGDP/RasGTP cycle

Mues

Roose

2016

Small GTPases

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T cell acute lymphoblastic leukemia/lymphoma (T-ALL) is an aggressive bone marrow cancer in children and adults, and chemotherapy often fails for relapsing patients. Molecularly targeted therapy is hindered by heterogeneity in T-ALL and mechanistic details of the affected pathways in T-ALL are needed. Deregulation of Ras signals is common in T-ALL. Ras is genetically mutated to a constitutively active form in about 15% of all haematopoietic malignancies, but there is a range of other ways to augment signaling through the Ras pathway. Several groups including our own uncovered that RasGRP1 overexpression leads to T-ALL in mouse models and in pediatric T-ALL patients, and we reported that this Ras guanine nucleotide exchange factor, RasGRP1, cooperates with cytokines to drive leukemogenesis. In our recent study by Ksionda et al. we analyzed the molecular details of cytokine receptor-RasGRP1-Ras signals in T-ALL and compared these to signals from mutated Ras alleles, which yielded several surprising results. Examples are the striking differences in flux through the RasGDP/RasGTP cycle in distinct T-ALL or unexpected differences in wiring of the Ras signaling pathway between T-ALL and normal developing T cells, which we will discuss here.

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Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity

et al. 2020

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RasGRP1 is a Ras guanine nucleotide exchange factor, and an essential regulator of lymphocyte receptor signaling. In mice, Rasgrp1 deletion results in defective T lymphocyte development. RASGRP1‐deficient patients suffer from immune deficiency, and the RASGRP1 gene has been linked to autoimmunity. However, how RasGRP1 levels are regulated, and if RasGRP1 dosage alterations contribute to autoimmunity remains unknown. We demonstrate that diminished Rasgrp1 expression caused defective T lymphocyte selection in C57BL/6 mice, and that the severity of inflammatory disease inversely correlates with Rasgrp1 expression levels. In patients with autoimmunity, active inflammation correlated with decreased RASGRP1 levels in CD4+ T cells. By analyzing H3K27 acetylation profiles in human T cells, we identified a RASGRP1 enhancer that harbors autoimmunity‐associated SNPs. CRISPR‐Cas9 disruption of this enhancer caused lower RasGRP1 expression, and decreased binding of RUNX1 and CBFB transcription factors. Analyzing patients with autoimmunity, we detected reduced RUNX1 expression in CD4+ T cells. Lastly, we mechanistically link RUNX1 to transcriptional regulation of RASGRP1 to reveal a key circuit regulating RasGRP1 expression, which is vital to prevent inflammatory disease.

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RasGRP Ras guanine nucleotide exchange factors in cancer

Cited by 51 publications

References 161 publications

Morpho/Proteomic Comparative between High Grade Pleomorphic Sarcoma and Metastasis Diagnosed in an Old Captive Common Hippo

Morpho/Proteomic Comparative between High Grade Pleomorphic Sarcoma and Metastasis Diagnosed in an Old Captive Common Hippo

Distinct oncogenic Ras signals characterized by profound differences in flux through the RasGDP/RasGTP cycle

Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity

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