RASD1
RASD1 | |||||||||||||||||
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Aliases | RASD1, AGS1, DEXRAS1, MGC:26290, ras related dexamethasone induced 1 | ||||||||||||||||
External IDs | MGI: 1270848 HomoloGene: 7509 GeneCards: RASD1 | ||||||||||||||||
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Species | Human | Mouse | |||||||||||||||
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Location (UCSC) | Chr 17: 17.49 – 17.5 Mb | Chr 11: 59.96 – 59.96 Mb | |||||||||||||||
PubMed search | [1] | [2] | |||||||||||||||
Wikidata |
View/Edit Human | View/Edit Mouse |
Dexamethasone-induced Ras-related protein 1 (RASD1) is a protein that in humans is encoded by the RASD1 gene on chromosome 17.[3][4] It is ubiquitously expressed in many tissues and cell types.[5] As a member of the Ras superfamily of small G-proteins, RASD1 regulates signal transduction pathways through both G proteins and G protein-coupled receptors.[6] RASD1 has been associated with several cancers.[7] The RASD1 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[8]
Structure
Gene
The RASD1 gene resides on chromosome 17 at the band 17p11.2 and contains 2 exons.[4] This gene produces 2 isoforms through alternative splicing.[9] A glucocorticoid response element (GRE) located in the 3'- flanking region of this gene allows glucocorticoids to induce expression of RASD1.[10]
Protein
This protein is a small GTPase belonging to the Ras superfamily.[9] As a Ras superfamily member, RASD1 shares several motifs characteristic of Ras proteins, including four highly conserved GTP binding pocket domains: the phosphate/magnesium binding regions GXXXXGK(S/T) (domain Σ1), DXXG (domain Σ2), and the guanine base binding loops NKXD (domain Σ3) and EXSAK (domain Σ4). These four domains, along with an effector loop, are responsible for binding to other proteins and signaling molecules. Another common Ras motif, the CAAX motif, can be found in the C-terminal of RASD1 and promotes the subcellular localization of RASD1 to the plasma membrane. As a GTPase, RASD1 also shares motifs, such as in the regions G-1 to G-3, with other GTPases. The full-length RASD1 cDNA produces a protein with a length of 280 amino acid residues and a molecular mass of 31.7 kDa.[10]
Function
RASD1 is expressed in many tissues including brain, heart, liver, and kidney. [11] [12] [13] It is also present in bone marrow, but its expression is absent or at very low levels in spleen, lymph node, and peripheral blood leukocytes. [13][14] RASD1 modulates multiple signaling cascades. RASD1 could activate G proteins in a receptor-independent manner and inhibit signal transduction through several different G protein-coupled receptors.[15] [16] Although RASD1 is a member of the Ras superfamily of small G-proteins, which often promotes cell growth and tumor expansion, it plays an active role in preventing aberrant cell growth.[14] It can be induced by corticosteroids and may play a role in the negative feedback loop controlling adrenocorticotropic hormone (ACTH) secretion.[17]In the hypothalamus, RASD1 expression is induced in two ways: one by elevated glucocorticoids in response to stress, and one in response to increased plasma osmolality resulting from osmotic stress. Based on its inhibitory actions on CREB phosphorylation, increased RASD1 in vasopressin-expressing neurons may be essential in controlling the transcriptional responses to stressors in both the supraoptic nucleus and paraventricular nucleus via modulation of the cAMP-PKA-CREB signaling pathway.[18] RASD1 is also reported to function with leptin in the activation of TRPC4 transient receptor potential channels and, thus, plays a role in regulating electrical excitability in gastrointestinal myocytes, pancreatic β-cells, and neurons.[19] In addition, the interaction between RASD1 and Ear2 is involved in renin transcriptional regulation.[20]
Clinical significance
In humans, upregulation of RASD1 leading to increased apoptosis has been observed in several human cancer cell lines such as DU-154 human prostate cancer cells[21] and in human breast cancer cells MCF-7.[7] In the latter, high concentrations of calycosin significantly suppressed the proliferation of MCF-7 cells, thereby promoting apoptosis of the cells. Moreover, compared with a control group, the expression of Bcl-2 decreased with calycosin while Bax increased, and these changes correlated with an elevated expression of RASD1. Together, it appears that, at relatively high concentrations, calycosin can trigger the mitochondrial apoptotic pathway by upregulating RASD1.[7]
Clinical marker
Additionally, in the cardiovascular field, a genome-wide analysis of common variants demonstrated a substantial overlap in the genetic risk of ischemic stroke and coronary artery disease, such as the link between RASD1 and other loci such as RAI1 and PEMT.[22] A multi-locus genetic risk score study based on a combination of 27 loci, including the RASD1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[8]
Interactions
RASD1 has been shown to interact with NOS1AP.[13]
References
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- ↑ St Croix B, Rago C, Velculescu V, Traverso G, Romans KE, Montgomery E, Lal A, Riggins GJ, Lengauer C, Vogelstein B, Kinzler KW (August 2000). "Genes expressed in human tumor endothelium". Science. 289 (5482): 1197–202. doi:10.1126/science.289.5482.1197. PMID 10947988.
- 1 2 "Entrez Gene: RASD1 RAS, dexamethasone-induced 1".
- ↑ "BioGPS - your Gene Portal System". biogps.org. Retrieved 2016-10-12.
- ↑ Graham TE, Prossnitz ER, Dorin RI (March 2002). "Dexras1/AGS-1 inhibits signal transduction from the Gi-coupled formyl peptide receptor to Erk-1/2 MAP kinases". The Journal of Biological Chemistry. 277 (13): 10876–82. doi:10.1074/jbc.M110397200. PMID 11751935.
- 1 2 3 Tian J, Duan YX, Bei CY, Chen J (August 2013). "Calycosin induces apoptosis by upregulation of RASD1 in human breast cancer cells MCF-7". Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Métabolisme. 45 (8): 593–8. doi:10.1055/s-0033-1341510. PMID 23609007.
- 1 2 Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, Nordio F, Hyde CL, Cannon CP, Sacks FM, Poulter NR, Sever PS, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS (June 2015). "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet. 385 (9984): 2264–71. doi:10.1016/S0140-6736(14)61730-X. PMID 25748612.
- 1 2 "RASD1 - Dexamethasone-induced Ras-related protein 1 precursor - Homo sapiens (Human) - RASD1 gene & protein". www.uniprot.org. Retrieved 2016-10-12.
- 1 2 Wie J, Kim BJ, Myeong J, Ha K, Jeong SJ, Yang D, Kim E, Jeon JH, So I (2015-01-01). "The Roles of Rasd1 small G proteins and leptin in the activation of TRPC4 transient receptor potential channels". Channels. 9 (4): 186–95. doi:10.1080/19336950.2015.1058454. PMID 26083271.
- ↑ Kemppainen RJ, Behrend EN (February 1998). "Dexamethasone rapidly induces a novel ras superfamily member-related gene in AtT-20 cells". The Journal of Biological Chemistry. 273 (6): 3129–31. PMID 9452419.
- ↑ Tu Y, Wu C (December 1999). "Cloning, expression and characterization of a novel human Ras-related protein that is regulated by glucocorticoid hormone". Biochimica et Biophysica Acta. 1489 (2-3): 452–6. PMID 10673050.
- 1 2 3 Fang M, Jaffrey SR, Sawa A, Ye K, Luo X, Snyder SH (October 2000). "Dexras1: a G protein specifically coupled to neuronal nitric oxide synthase via CAPON". Neuron. 28 (1): 183–93. PMID 11086993.
- 1 2 Vaidyanathan G, Cismowski MJ, Wang G, Vincent TS, Brown KD, Lanier SM (July 2004). "The Ras-related protein AGS1/RASD1 suppresses cell growth". Oncogene. 23 (34): 5858–63. doi:10.1038/sj.onc.1207774. PMID 15184869.
- ↑ Takesono A, Nowak MW, Cismowski M, Duzic E, Lanier SM (April 2002). "Activator of G-protein signaling 1 blocks GIRK channel activation by a G-protein-coupled receptor: apparent disruption of receptor signaling complexes". The Journal of Biological Chemistry. 277 (16): 13827–30. doi:10.1074/jbc.M201064200. PMID 11842095.
- ↑ Graham TE, Prossnitz ER, Dorin RI (March 2002). "Dexras1/AGS-1 inhibits signal transduction from the Gi-coupled formyl peptide receptor to Erk-1/2 MAP kinases". The Journal of Biological Chemistry. 277 (13): 10876–82. doi:10.1074/jbc.M110397200. PMID 11751935.
- ↑ Brogan MD, Behrend EN, Kemppainen RJ (October 2001). "Regulation of Dexras1 expression by endogenous steroids". Neuroendocrinology. 74 (4): 244–50. PMID 11598380.
- ↑ Greenwood MP, Greenwood M, Mecawi AS, Antunes-Rodrigues J, Paton JF, Murphy D (January 2016). "Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation". Molecular Brain. 9: 1. doi:10.1186/s13041-015-0182-2. PMID 26739966.
- ↑ Wie J, Kim BJ, Myeong J, Ha K, Jeong SJ, Yang D, Kim E, Jeon JH, So I (2015). "The Roles of Rasd1 small G proteins and leptin in the activation of TRPC4 transient receptor potential channels". Channels. 9 (4): 186–95. doi:10.1080/19336950.2015.1058454. PMID 26083271.
- ↑ Tan JJ, Ong SA, Chen KS (19 January 2011). "Rasd1 interacts with Ear2 (Nr2f6) to regulate renin transcription". BMC Molecular Biology. 12: 4. doi:10.1186/1471-2199-12-4. PMID 21247419.
- ↑ Liu XJ, Li YQ, Chen QY, Xiao SJ, Zeng SE (2014-01-01). "Up-regulating of RASD1 and apoptosis of DU-145 human prostate cancer cells induced by formononetin in vitro". Asian Pacific Journal of Cancer Prevention. 15 (6): 2835–9. PMID 24761910.
- ↑ Dichgans M, Malik R, König IR, Rosand J, Clarke R, Gretarsdottir S, et al. (January 2014). "Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants". Stroke; A Journal of Cerebral Circulation. 45 (1): 24–36. doi:10.1161/STROKEAHA.113.002707. PMID 24262325.
Further reading
- Kemppainen RJ, Behrend EN (Feb 1998). "Dexamethasone rapidly induces a novel ras superfamily member-related gene in AtT-20 cells". The Journal of Biological Chemistry. 273 (6): 3129–31. doi:10.1074/jbc.273.6.3129. PMID 9452419.
- Cismowski MJ, Takesono A, Ma C, Lizano JS, Xie X, Fuernkranz H, Lanier SM, Duzic E (Sep 1999). "Genetic screens in yeast to identify mammalian nonreceptor modulators of G-protein signaling". Nature Biotechnology. 17 (9): 878–83. doi:10.1038/12867. PMID 10471929.
- Tu Y, Wu C (Dec 1999). "Cloning, expression and characterization of a novel human Ras-related protein that is regulated by glucocorticoid hormone". Biochimica et Biophysica Acta. 1489 (2-3): 452–6. doi:10.1016/s0167-4781(99)00197-9. PMID 10673050.
- Cismowski MJ, Ma C, Ribas C, Xie X, Spruyt M, Lizano JS, Lanier SM, Duzic E (Aug 2000). "Activation of heterotrimeric G-protein signaling by a ras-related protein. Implications for signal integration". The Journal of Biological Chemistry. 275 (31): 23421–4. doi:10.1074/jbc.C000322200. PMID 10840027.
- Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
- Fang M, Jaffrey SR, Sawa A, Ye K, Luo X, Snyder SH (Oct 2000). "Dexras1: a G protein specifically coupled to neuronal nitric oxide synthase via CAPON". Neuron. 28 (1): 183–93. doi:10.1016/S0896-6273(00)00095-7. PMID 11086993.
- Ognjanovic S, Bao S, Yamamoto SY, Garibay-Tupas J, Samal B, Bryant-Greenwood GD (Apr 2001). "Genomic organization of the gene coding for human pre-B-cell colony enhancing factor and expression in human fetal membranes". Journal of Molecular Endocrinology. 26 (2): 107–17. doi:10.1677/jme.0.0260107. PMID 11241162.
- Takesono A, Nowak MW, Cismowski M, Duzic E, Lanier SM (Apr 2002). "Activator of G-protein signaling 1 blocks GIRK channel activation by a G-protein-coupled receptor: apparent disruption of receptor signaling complexes". The Journal of Biological Chemistry. 277 (16): 13827–30. doi:10.1074/jbc.M201064200. PMID 11842095.
- Bi W, Yan J, Stankiewicz P, Park SS, Walz K, Boerkoel CF, Potocki L, Shaffer LG, Devriendt K, Nowaczyk MJ, Inoue K, Lupski JR (May 2002). "Genes in a refined Smith-Magenis syndrome critical deletion interval on chromosome 17p11.2 and the syntenic region of the mouse". Genome Research. 12 (5): 713–28. doi:10.1101/gr.73702. PMC 186594. PMID 11997338.
- Jaffrey SR, Fang M, Snyder SH (Dec 2002). "Nitrosopeptide mapping: a novel methodology reveals s-nitrosylation of dexras1 on a single cysteine residue". Chemistry & Biology. 9 (12): 1329–35. doi:10.1016/S1074-5521(02)00293-4. PMID 12498886.
- Kemppainen RJ, Cox E, Behrend EN, Brogan MD, Ammons JM (Jun 2003). "Identification of a glucocorticoid response element in the 3'-flanking region of the human Dexras1 gene". Biochimica et Biophysica Acta. 1627 (2-3): 85–9. doi:10.1016/s0167-4781(03)00079-4. PMID 12818426.
- Vaidyanathan G, Cismowski MJ, Wang G, Vincent TS, Brown KD, Lanier SM (Jul 2004). "The Ras-related protein AGS1/RASD1 suppresses cell growth". Oncogene. 23 (34): 5858–63. doi:10.1038/sj.onc.1207774. PMID 15184869.
- Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A (Oct 2004). "From ORFeome to biology: a functional genomics pipeline". Genome Research. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
- Hiskens R, Vatish M, Hill C, Davey J, Ladds G (Dec 2005). "Specific in vivo binding of activator of G protein signalling 1 to the Gbeta1 subunit". Biochemical and Biophysical Research Communications. 337 (4): 1038–46. doi:10.1016/j.bbrc.2005.09.149. PMID 16225846.
- Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S (Jan 2006). "The LIFEdb database in 2006". Nucleic Acids Research. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.
- Nguyen CH, Watts VJ (May 2006). "Dexamethasone-induced Ras protein 1 negatively regulates protein kinase C delta: implications for adenylyl cyclase 2 signaling". Molecular Pharmacology. 69 (5): 1763–71. doi:10.1124/mol.105.019133. PMID 16489124.
- Compton SL, Kemppainen RJ, Behrend EN (Dec 2009). "Prenylated Rab acceptor domain family member 1 is involved in stimulated ACTH secretion and inhibition". Cellular Signalling. 21 (12): 1901–9. doi:10.1016/j.cellsig.2009.08.007. PMID 19733236.