RASD1

Dexamethasone-induced Ras-related protein 1 (RASD1) is a protein that in humans is encoded by the RASD1 gene on chromosome 17.[5][6] It is ubiquitously expressed in many tissues and cell types.[7] 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.[8] RASD1 has been associated with several cancers.[9] The RASD1 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[10]

RASD1
Identifiers
AliasesRASD1, AGS1, DEXRAS1, MGC:26290, ras related dexamethasone induced 1
External IDsOMIM: 605550 MGI: 1270848 HomoloGene: 7509 GeneCards: RASD1
Gene location (Human)
Chr.Chromosome 17 (human)[1]
Band17p11.2Start17,494,437 bp[1]
End17,496,395 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

51655

19416

Ensembl

ENSG00000108551

ENSMUSG00000049892

UniProt

Q9Y272

O35626

RefSeq (mRNA)

NM_016084
NM_001199989

NM_009026

RefSeq (protein)

NP_001186918
NP_057168

NP_033052

Location (UCSC)Chr 17: 17.49 – 17.5 MbChr 11: 59.96 – 59.96 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

Gene

The RASD1 gene resides on chromosome 17 at the band 17p11.2 and contains 2 exons.[6] This gene produces 2 isoforms through alternative splicing.[11] A glucocorticoid response element (GRE) located in the 3'- flanking region of this gene allows glucocorticoids to induce expression of RASD1.[12]

Protein

This protein is a small GTPase belonging to the Ras superfamily.[11] 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.[12]

Function

RASD1 is expressed in many tissues including brain, heart, liver, and kidney.[13][14][15] 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.[15][16] 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.[17][8] 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.[16] It can be induced by corticosteroids and may play a role in the negative feedback loop controlling adrenocorticotropic hormone (ACTH) secretion.[18] 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.[19] 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.[20] In addition, the interaction between RASD1 and Ear2 is involved in renin transcriptional regulation.[21]

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[22] and in human breast cancer cells MCF-7.[9] 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.[9]

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.[23] 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).[10]

Interactions

RASD1 has been shown to interact with NOS1AP.[15]

References
  1. GRCh38: Ensembl release 89: ENSG00000108551 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000049892 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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. Bibcode:2000Sci...289.1197S. doi:10.1126/science.289.5482.1197. PMID 10947988.
  6. "Entrez Gene: RASD1 RAS, dexamethasone-induced 1".
  7. "BioGPS - your Gene Portal System". biogps.org. Retrieved 2016-10-12.
  8. 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.
  9. 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.
  10. 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. PMC 4608367. PMID 25748612.
  11. "RASD1 - Dexamethasone-induced Ras-related protein 1 precursor - Homo sapiens (Human) - RASD1 gene & protein". www.uniprot.org. Retrieved 2016-10-12.
  12. 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. PMC 4594510. PMID 26083271.
  13. 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. doi:10.1074/jbc.273.6.3129. PMID 9452419.
  14. 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 (BBA) - Gene Structure and Expression. 1489 (2–3): 452–6. doi:10.1016/s0167-4781(99)00197-9. PMID 10673050.
  15. 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. doi:10.1016/S0896-6273(00)00095-7. PMID 11086993. S2CID 10533464.
  16. 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.
  17. 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.
  18. Brogan MD, Behrend EN, Kemppainen RJ (October 2001). "Regulation of Dexras1 expression by endogenous steroids". Neuroendocrinology. 74 (4): 244–50. doi:10.1159/000054691. PMID 11598380. S2CID 19846824.
  19. 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. PMC 4704412. PMID 26739966.
  20. 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. PMC 4594510. PMID 26083271.
  21. 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. PMC 3036621. PMID 21247419.
  22. 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. doi:10.7314/apjcp.2014.15.6.2835. PMID 24761910.
  23. 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. PMC 4112102. PMID 24262325.

Further reading
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