977:
nonimprinted allele (the paternal copy) confers a loss of ARHI expression. Although LOH has been reported in 40% of ovarian and breast cancers, another typical mechanism of gene silencing is through methylation. Since ARHI expression is decreased in 70% of invasive breast cancer, aberrant methylation is almost certainly the other common mechanism through which the gene is silenced. Found in "ARHI" are three CpG islands, which are common sites of epigenetic regulation, and hypermethylation of these regions in other tumor suppressor genes have been observed in various cancers. For example, decreased expression of BRCA1 in cancerous tissue has been linked with hypermethylation of the "BRCA1" promoter. Indeed, hypermethylation of certain CpG islands were associated with decreased expression of ARHI, and the protein showed a corresponding re-expression after demethylation of the regions.
119:
144:
937:, it is absent in cancers found in these tissues where no expression of ARHI has been detected. In non-cancerous cells growth factor signals associate ARHI N- and C-terminally to the plasma membrane, where it can interact with C-RAF. This interaction inhibits the activation of MEK and ERK and even cell migration. In cancer tissues, where ARHI is not expressed, cells will thus migrate; this possibly is a cause for metastasis especially in breast cancer.
150:
984:
model proposed by
Knudson is reduced to a more susceptible situation. The nonexpression of the maternal allele leaves the gene only one “strike” in terms of any number of mutational mechanisms, the two most common being LOH and hypermethylation of the gene promoter. In this way, the imprinted "ARHI"
889:
extension. This sequence is not generally found in the Ras superfamily, most of which show no inhibitory activity towards cell growth and even act as positive growth regulators. Deletion of this tail results in a significant drop in ARHI's ability to inhibit cell growth. This change in structure has
976:
The "ARHI" gene is maternally imprinted (expressed monoallelically) and mapped specifically to 1p31, which is a common site for loss of heterozygosity (LOH). This locus on chromosome 1 is the most frequent deletion in breast and ovarian cancers. Because this gene is maternally imprinted, LOH of the
944:
is an essential protein in the cell's progression from G1 to S phase, and its regulation by ARHI is critical in maintaining healthy cells. This is the mechanism by which ARHI inhibits cell growth and acts as a negative growth regulator. A loss of ARHI function could result in out-of-control cell
875:
While ARHI is structurally similar to other GTPase proteins, its function is remarkably different from Ras. Ras is an oncogenic protein involved in cellular proliferation and signal transduction, and while the Ras superfamily generally consists of positive growth regulators,
880:
is a tumor-suppressor gene. In contrast to Ras, ARHI works as an inhibitor for cell growth, thus functioning as a negative growth regulator. ARHI has also been shown to have less GTPase activity than most Ras proteins even though the proteins share a very similar structure.
1548:
Li BX, Li J, Luo CL, Zhang MC, Li H, Li LL, Xu HF, Shen YW, Xue AM, Zhao ZQ (Mar 2013). "Expression of JMJD2A in infiltrating duct carcinoma was markedly higher than fibroadenoma, and associated with expression of ARHI, p53 and ER in infiltrating duct carcinoma".
1344:
Yuan J, Luo RZ, Fujii S, Wang L, Hu W, Andreeff M, Pan Y, Kadota M, Oshimura M, Sahin AA, Issa JP, Bast RC, Yu Y (Jul 2003). "Aberrant methylation and silencing of ARHI, an imprinted tumor suppressor gene in which the function is lost in breast cancers".
1114:
Yuan J, Luo RZ, Fujii S, Wang L, Hu W, Andreeff M, Pan Y, Kadota M, Oshimura M, Sahin AA, Issa JP, Bast RC, Yu Y (Jul 2003). "Aberrant methylation and silencing of ARHI, an imprinted tumor suppressor gene in which the function is lost in breast cancers".
884:
The underlying cause for these dramatic differences in function is thought to be structural variations between ARHI and the Ras superfamily. The negative growth regulation exhibited by ARHI is most likely due to a unique 34-amino-acid
819:
gene, with monoallelic expression of the paternal allele, which is associated with growth suppression. Thus, this gene appears to be a putative tumor suppressor gene whose function is abrogated in ovarian and breast cancers.
1489:
Pei XH, Yang Z, Liu HX, Qiao SS (Oct 2011). "Aplasia Ras homologue member I overexpression induces apoptosis through inhibition of survival pathways in human hepatocellular carcinoma cells in culture and in xenograft".
1252:
Klingauf M, Beck M, Berge U, Turgay Y, Heinzer S, Horvath P, Kroschewski R (Nov 2012). "The tumour suppressor DiRas3 interacts with C-RAF and downregulates MEK activity to restrict cell migration".
890:
no effect on protein expression levels or its GTP-binding ability, suggesting the extension's primary function is giving rise to this protein's negative growth regulation.
157:
1633:
80:
527:
1301:"The tumor suppressor DiRas3 forms a complex with H-Ras and C-RAF proteins and regulates localization, dimerization, and kinase activity of C-RAF"
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is introduced into cancer cells lacking this gene, many responses occur in addition to cyclin D1 down-regulation. These include induction of
1026:
1653:
901:. These residues are highly conserved in other Ras proteins, and are critical for the GTPase activity. In Ras, they are specifically
736:
1013:
925:. While ARHI still binds GTP with high affinity, its hydrolysis of GTP to GDP is relatively low because of these differences.
1149:"ARHI is a Ras-related small G-protein with a novel N-terminal extension that inhibits growth of ovarian and breast cancers"
143:
118:
867:, two other small GTP binding proteins. Reduced expression of DIRAS3 has been reported in 70% of invasive breast cancers.
1368:"Expression of the tumor suppressor ARHI inhibits the growth of pancreatic cancer cells by inducing G1 cell cycle arrest"
1009:
815:
and is expressed in normal ovarian and breast epithelial cells but not in ovarian and breast cancers. It is a maternally
68:
156:
149:
1570:
Janssen EA, Øvestad IT, Skaland I, Søiland H, Gudlaugsson E, Kjellevold KH, Nysted A, Søreide JA, Baak JP (2009).
1401:
Yu Y, Xu F, Peng H, Fang X, Zhao S, Li Y, Cuevas B, Kuo WL, Gray JW, Siciliano M, Mills GB, Bast RC (Jan 1999).
1193:
Yu Y, Xu F, Peng H, Fang X, Zhao S, Li Y, Cuevas B, Kuo WL, Gray JW, Siciliano M, Mills GB, Bast RC (Jan 1999).
1624:
893:
The reduced GTPase activity observed in ARHI is thought to arise from critical differences in three specific
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570:
940:
ARHI influences also the cell cycle, specifically ARHI's strong inhibition of the cyclin D1 promoter.
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1583:
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1422:
1403:"NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas"
1379:
1322:
1312:
1299:
Baljuls A, Beck M, Oenel A, Robubi A, Kroschewski R, Hekman M, Rudel T, Rapp UR (Jun 2012).
1261:
1224:
1214:
1195:"NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas"
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gene has a high risk of conferring cancers due to its susceptibility to mutations and
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Luo RZ, Fang X, Marquez R, Liu SY, Mills GB, Liao WS, Yu Y, Bast RC (May 2003).
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National Center for
Biotechnology Information, U.S. National Library of Medicine
946:
1407:
Proceedings of the
National Academy of Sciences of the United States of America
1199:
Proceedings of the
National Academy of Sciences of the United States of America
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protein-coding region that encodes a 26-kDa protein. The DIRAS3 protein is a
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848:
491:
329:
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182:
84:
1605:
1572:"LOH at 1p31 (ARHI) and proliferation in lymph node-negative breast cancer"
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in ovarian cancers and invasive breast carcinomas when ARHI is found to be
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regulation of cyclin-dependent protein serine/threonine kinase activity
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Shi Z, Zhou X, Xu L, Zhang T, Hou Y, Zhu W, Zhang T (Sep 2002). "".
933:
While ARHI is constitutively expressed in normal ovarian and breast
1454:
Yang J, Hu A, Wang L, Li B, Chen Y, Zhao W, Xu W, Li T (Jun 2009).
1064:
Yang J, Hu A, Wang L, Li B, Chen Y, Zhao W, Xu W, Li T (Jun 2009).
1456:"NOEY2 mutations in primary breast cancers and breast hyperplasia"
1066:"NOEY2 mutations in primary breast cancers and breast hyperplasia"
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476:
472:
805:
72:
913:. ARHI has three different amino acids in the effector domain:
962:
958:
969:. Thus, loss of any of these processes (arising from loss of
219:
341:
1048:"Entrez Gene: DIRAS family, GTP-binding RAS-like 3"
855:belonging to the Ras superfamily and shares 50–60%
714:
693:
669:
648:
447:
regulation of gene expression by genetic imprinting
1005:
1003:
1001:
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1366:Lu X, Qian J, Yu Y, Yang H, Li J (Sep 2009).
8:
1010:GRCh38: Ensembl release 89: ENSG00000162595
1634:United States National Library of Medicine
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1623:at the U.S. National Library of Medicine
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462:small GTPase mediated signal transduction
1632:This article incorporates text from the
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1184:
1042:
1040:
945:growth and, in fact, cyclin D1 is often
804:that in humans is encoded by the DIRAS3
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27:Mammalian protein found in Homo sapiens
1551:Indian Journal of Experimental Biology
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7:
965:, and reduced signaling through the
59:, ARHI, NOEY2, DIRAS family GTPase 3
1305:The Journal of Biological Chemistry
980:Because the gene is imprinted, the
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431:intracellular anatomical structure
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330:More reference expression data
1:
811:This gene is a member of the
798:aplysia ras homology member I
140:
1473:10.1016/j.breast.2009.04.004
1083:10.1016/j.breast.2009.04.004
1654:Genes on human chromosome 1
794:GTP-binding protein Di-Ras3
1670:
1529:Zhonghua Zhong Liu Za Zhi
1492:Cell Biology International
1027:"Human PubMed Reference:"
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1625:Medical Subject Headings
1318:10.1074/jbc.M112.343780
796:(DIRAS3) also known as
737:Chr 1: 68.05 – 68.05 Mb
1166:10.1038/sj.onc.1206380
973:) can lead to cancer.
871:Structure and function
1588:10.3233/CLO-2009-0479
1428:10.1073/pnas.96.1.214
1266:10.1111/boc.201200030
1220:10.1073/pnas.96.1.214
982:two-hit tumorigenesis
1621:NOEY2+protein,+human
823:DIRAS3 is linked to
297:right adrenal cortex
133:Chromosome 1 (human)
1504:10.1042/CBI20110023
1419:1999PNAS...96..214Y
1385:10.3892/or_00000483
1254:Biology of the Cell
1211:1999PNAS...96..214Y
895:amino acid residues
457:signal transduction
293:germinal epithelium
1636:, which is in the
835:gene includes one
440:Biological process
414:Cellular component
385:nucleotide binding
378:Molecular function
261:anterior pituitary
97:DIRAS3 - orthologs
1576:Cellular Oncology
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1372:Oncology Reports
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961:, activation of
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1347:Cancer Research
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1292:Further reading
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967:Ras/MAP pathway
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813:Ras superfamily
780:View/Edit Human
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732:Location (UCSC)
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929:Role in cancer
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240:
238:
234:
232:
231:
227:
226:
223:
221:
217:
213:
209:
205:
197:
192:
188:
184:
179:
169:
165:
158:
151:
145:
138:
134:
128:
124:
120:
115:
111:
106:
102:
98:
94:
90:
86:
82:
78:
74:
70:
62:
57:
50:
45:
40:
36:
31:
19:
1631:
1630:
1579:
1575:
1554:
1550:
1535:(5): 475–8.
1532:
1528:
1495:
1491:
1463:
1459:
1413:(1): 214–9.
1410:
1406:
1375:
1371:
1350:
1346:
1308:
1304:
1257:
1253:
1247:
1205:(1): 214–9.
1202:
1198:
1156:
1152:
1120:
1116:
1073:
1069:
1030:
1021:
979:
975:
970:
954:
947:up-regulated
939:
932:
892:
883:
877:
874:
832:
822:
810:
800:(ARHI) is a
797:
793:
792:
719:
698:
674:
653:
631:
612:
588:
569:
545:
526:
506:
501:
265:hypothalamus
235:
228:
64:External IDs
847:with a 687
827:as well as
405:GDP binding
390:GTP binding
277:right ovary
194:68,051,717
181:68,045,886
42:Identifiers
1016:, May 2017
993:References
987:epigenetic
887:N-terminus
269:left ovary
239:(ortholog)
77:HomoloGene
942:Cyclin D1
817:imprinted
701:NP_004666
656:NM_004675
492:Orthologs
85:GeneCards
1648:Category
1606:19759414
1563:23678541
1541:12485503
1520:12811622
1512:21933150
1482:19482475
1394:19639215
1359:12874023
1337:22605333
1282:19790001
1274:23157514
1175:12771940
1153:Oncogene
1129:12874023
1092:19482475
1012:–
857:homology
843:and one
837:promoter
769:Wikidata
471:Sources:
426:membrane
1597:4619107
1447:9874798
1415:Bibcode
1328:3391090
1239:9874798
1207:Bibcode
1014:Ensembl
953:. When
897:in the
802:protein
600:UniProt
557:Ensembl
498:Species
477:QuickGO
214:pattern
49:Aliases
1627:(MeSH)
1604:
1594:
1561:
1539:
1518:
1510:
1480:
1460:Breast
1445:
1435:
1392:
1357:
1335:
1325:
1280:
1272:
1237:
1227:
1173:
1127:
1090:
1070:Breast
921:, and
909:, and
853:GTPase
845:intron
839:, two
833:DIRAS3
831:. The
752:search
750:PubMed
614:O95661
514:Entrez
342:BioGPS
281:oocyte
173:1p31.3
89:DIRAS3
73:605193
56:DIRAS3
33:DIRAS3
18:DIRAS3
1516:S2CID
1438:15119
1278:S2CID
1230:15119
859:with
841:exons
507:Mouse
502:Human
473:Amigo
237:Mouse
230:Human
177:Start
110:Human
81:48296
1602:PMID
1559:PMID
1537:PMID
1508:PMID
1478:PMID
1443:PMID
1390:PMID
1355:PMID
1333:PMID
1270:PMID
1235:PMID
1171:PMID
1125:PMID
1088:PMID
971:ARHI
955:ARHI
878:ARHI
863:and
806:gene
528:9077
220:Bgee
168:Band
127:Chr.
69:OMIM
1592:PMC
1584:doi
1500:doi
1468:doi
1433:PMC
1423:doi
1380:doi
1323:PMC
1313:doi
1309:287
1262:doi
1258:105
1225:PMC
1215:doi
1161:doi
1078:doi
963:JNK
959:p21
865:Rap
861:Ras
758:n/a
743:n/a
721:n/a
676:n/a
632:n/a
589:n/a
546:n/a
350:n/a
317:n/a
190:End
93:OMA
1650::
1600:.
1590:.
1580:31
1578:.
1574:.
1555:51
1553:.
1533:24
1531:.
1514:.
1506:.
1496:35
1494:.
1476:.
1464:18
1462:.
1458:.
1441:.
1431:.
1421:.
1411:96
1409:.
1405:.
1388:.
1376:22
1374:.
1370:.
1351:63
1349:.
1331:.
1321:.
1307:.
1303:.
1276:.
1268:.
1256:.
1233:.
1223:.
1213:.
1203:96
1201:.
1197:.
1183:^
1169:.
1157:22
1155:.
1151:.
1137:^
1121:63
1119:.
1100:^
1086:.
1074:18
1072:.
1068:.
1056:^
1039:^
1029:.
1000:^
917:,
905:,
849:bp
808:.
475:/
196:bp
183:bp
91:;
87::
83:;
79::
75:;
71::
1640:.
1608:.
1586::
1565:.
1543:.
1522:.
1502::
1484:.
1470::
1449:.
1425::
1417::
1396:.
1382::
1361:.
1339:.
1315::
1284:.
1264::
1241:.
1217::
1209::
1177:.
1163::
1131:.
1094:.
1080::
1050:.
1033:.
923:G
919:K
915:A
911:Q
907:A
903:G
112:)
95::
20:)
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