RASD1 explained

Dexamethasone-induced Ras-related protein 1 (RASD1) is a protein that in humans is encoded by the RASD1 gene on chromosome 17.[1] [2] It is ubiquitously expressed in many tissues and cell types.[3] 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. RASD1 has been associated with several cancers. The RASD1 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

Structure

Gene

The RASD1 gene resides on chromosome 17 at the band 17p11.2 and contains 2 exons. This gene produces 2 isoforms through alternative splicing.[4] A glucocorticoid response element (GRE) located in the 3'- flanking region of this gene allows glucocorticoids to induce expression of RASD1.[5]

Protein

This protein is a small GTPase belonging to the Ras superfamily. 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.

Function

RASD1 is expressed in many tissues including brain, heart, liver, and kidney.[6] [7] [8] 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.[9] 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.[10] [11] 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.[9] It can be induced by corticosteroids and may play a role in the negative feedback loop controlling adrenocorticotropic hormone (ACTH) secretion.[12] 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.[13] 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.[14] In addition, the interaction between RASD1 and Ear2 is involved in renin transcriptional regulation.[15]

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[16] and in human breast cancer cells MCF-7.[17] 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.[17]

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.[18] 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).[19]

Interactions

RASD1 has been shown to interact with NOS1AP.[8]

Further reading

Notes and References

  1. St Croix B, Rago C, Velculescu V, Traverso G, Romans KE, Montgomery E, Lal A, Riggins GJ, Lengauer C, Vogelstein B, Kinzler KW . Genes expressed in human tumor endothelium . Science . 289 . 5482 . 1197–202 . August 2000 . 10947988 . 10.1126/science.289.5482.1197 . 2000Sci...289.1197S .
  2. Web site: Entrez Gene: RASD1 RAS, dexamethasone-induced 1.
  3. Web site: BioGPS - your Gene Portal System. biogps.org. 2016-10-12.
  4. Web site: RASD1 - Dexamethasone-induced Ras-related protein 1 precursor - Homo sapiens (Human) - RASD1 gene & protein. www.uniprot.org. 2016-10-12.
  5. Wie J, Kim BJ, Myeong J, Ha K, Jeong SJ, Yang D, Kim E, Jeon JH, So I . The Roles of Rasd1 small G proteins and leptin in the activation of TRPC4 transient receptor potential channels . Channels . 9 . 4 . 186–95 . 2015-01-01 . 26083271 . 10.1080/19336950.2015.1058454 . 4594510.
  6. Kemppainen RJ, Behrend EN . Dexamethasone rapidly induces a novel ras superfamily member-related gene in AtT-20 cells . The Journal of Biological Chemistry . 273 . 6 . 3129–31 . February 1998 . 9452419 . 10.1074/jbc.273.6.3129. free .
  7. Tu Y, Wu C . 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 . December 1999 . 10673050 . 10.1016/s0167-4781(99)00197-9.
  8. Fang M, Jaffrey SR, Sawa A, Ye K, Luo X, Snyder SH . Dexras1: a G protein specifically coupled to neuronal nitric oxide synthase via CAPON . Neuron . 28 . 1 . 183–93 . October 2000 . 11086993 . 10.1016/S0896-6273(00)00095-7. 10533464 . free .
  9. Vaidyanathan G, Cismowski MJ, Wang G, Vincent TS, Brown KD, Lanier SM . The Ras-related protein AGS1/RASD1 suppresses cell growth . Oncogene . 23 . 34 . 5858–63 . July 2004 . 15184869 . 10.1038/sj.onc.1207774 . 32901324 .
  10. Takesono A, Nowak MW, Cismowski M, Duzic E, Lanier SM . 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 . April 2002 . 11842095 . 10.1074/jbc.M201064200 . free .
  11. Graham TE, Prossnitz ER, Dorin RI . 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 . March 2002 . 11751935 . 10.1074/jbc.M110397200 . free .
  12. Brogan MD, Behrend EN, Kemppainen RJ . Regulation of Dexras1 expression by endogenous steroids . Neuroendocrinology . 74 . 4 . 244–50 . October 2001 . 11598380 . 10.1159/000054691. 19846824 .
  13. Greenwood MP, Greenwood M, Mecawi AS, Antunes-Rodrigues J, Paton JF, Murphy D . Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation . Molecular Brain . 9 . 1 . January 2016 . 26739966 . 10.1186/s13041-015-0182-2 . 4704412 . free .
  14. Wie J, Kim BJ, Myeong J, Ha K, Jeong SJ, Yang D, Kim E, Jeon JH, So I . The Roles of Rasd1 small G proteins and leptin in the activation of TRPC4 transient receptor potential channels . Channels . 9 . 4 . 186–95 . 2015 . 26083271 . 10.1080/19336950.2015.1058454 . 4594510.
  15. Tan JJ, Ong SA, Chen KS . Rasd1 interacts with Ear2 (Nr2f6) to regulate renin transcription . BMC Molecular Biology . 12 . 4 . 19 January 2011 . 21247419 . 10.1186/1471-2199-12-4 . 3036621 . free .
  16. Liu XJ, Li YQ, Chen QY, Xiao SJ, Zeng SE . 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 . 2014-01-01 . 24761910 . 10.7314/apjcp.2014.15.6.2835. free .
  17. Tian J, Duan YX, Bei CY, Chen J . Calycosin induces apoptosis by upregulation of RASD1 in human breast cancer cells MCF-7 . Hormone and Metabolic Research . 45 . 8 . 593–8 . August 2013 . 23609007 . 10.1055/s-0033-1341510 . 206346475 .
  18. Dichgans M, Malik R, König IR, Rosand J, Clarke R, Gretarsdottir S, Thorleifsson G, Mitchell BD, Assimes TL, Levi C, O'Donnell CJ, Fornage M, Thorsteinsdottir U, Psaty BM, Hengstenberg C, Seshadri S, Erdmann J, Bis JC, Peters A, Boncoraglio GB, März W, Meschia JF, Kathiresan S, Ikram MA, McPherson R, Stefansson K, Sudlow C, Reilly MP, Thompson JR, Sharma P, Hopewell JC, Chambers JC, Watkins H, Rothwell PM, Roberts R, Markus HS, Samani NJ, Farrall M, Schunkert H . 6 . 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 . January 2014 . 24262325 . 10.1161/STROKEAHA.113.002707 . 4112102.
  19. 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 . 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 . June 2015 . 25748612 . 10.1016/S0140-6736(14)61730-X . 4608367.

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