DIRAS3 (gene)

Last updated
DIRAS3
Identifiers
Aliases DIRAS3 , ARHI, NOEY2, DIRAS family GTPase 3
External IDs OMIM: 605193 HomoloGene: 48296 GeneCards: DIRAS3
Orthologs
SpeciesHumanMouse
Entrez

9077

n/a

Ensembl

ENSG00000162595

n/a

UniProt

O95661

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RefSeq (mRNA)

NM_004675

n/a

RefSeq (protein)

NP_004666

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Location (UCSC) Chr 1: 68.05 – 68.05 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

GTP-binding protein Di-Ras3 (DIRAS3) also known as aplysia ras homology member I (ARHI) is a protein that in humans is encoded by the DIRAS3 gene. [3]

Contents

This gene is a member of the Ras superfamily and is expressed in normal ovarian and breast epithelial cells but not in ovarian and breast cancers. It is a maternally imprinted 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. [3]

DIRAS3 is linked to breast cancer as well as ovarian cancer. The DIRAS3 gene includes one promoter, two exons and one intron with a 687 bp protein-coding region that encodes a 26-kDa protein. [4] The DIRAS3 protein is a GTPase belonging to the Ras superfamily and shares 50–60% homology with Ras and Rap, two other small GTP binding proteins. [4] Reduced expression of DIRAS3 has been reported in 70% of invasive breast cancers. [5]

Structure and function

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, ARHI 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. [6]

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 N-terminus 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 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.

The reduced GTPase activity observed in ARHI is thought[ by whom? ] to arise from critical differences in three specific amino acid residues in the effector domain. These residues are highly conserved in other Ras proteins, and are critical for the GTPase activity. In Ras, they are specifically G 12, A 59, and Q 61. ARHI has three different amino acids in the effector domain: A 46, K 93, and G 95. While ARHI still binds GTP with high affinity, its hydrolysis of GTP to GDP is relatively low because of these differences.

Role in cancer

While ARHI is constitutively expressed in normal ovarian and breast epithelial cells, it is absent in cancers found in these tissues where no expression of ARHI has been detected. [7] 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. [8] In cancer tissues, where ARHI is not expressed, cells will thus migrate; this possibly is a cause for metastasis especially in breast cancer.

ARHI influences also the cell cycle, specifically ARHI's strong inhibition of the cyclin D1 promoter. [7] Cyclin D1 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 growth and, in fact, cyclin D1 is often up-regulated in ovarian cancers and invasive breast carcinomas when ARHI is found to be down-regulated. [7] When ARHI is introduced into cancer cells lacking this gene, many responses occur in addition to cyclin D1 down-regulation. [6] These include induction of p21, activation of JNK, and reduced signaling through the Ras/MAP pathway. [6] Thus, loss of any of these processes (arising from loss of ARHI) can lead to cancer.

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 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. [5] 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. [5] 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. [5]

Because the gene is imprinted, the two-hit tumorigenesis 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. [5] In this way, the imprinted "ARHI" gene has a high risk of conferring cancers due to its susceptibility to mutations and epigenetic modifications.

Related Research Articles

Ras GTPase GTP-binding proteins functioning on cell-cycle regulation

Ras, from "Rat sarcoma virus", is a family of related proteins that are expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells. Ras is the prototypical member of the Ras superfamily of proteins, which are all related in three-dimensional structure and regulate diverse cell behaviours.

GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event. GAPs are also known as RGS protein, or RGS proteins, and these proteins are crucial in controlling the activity of G proteins. Regulation of G proteins is important because these proteins are involved in a variety of important cellular processes. The large G proteins, for example, are involved in transduction of signaling from the G protein-coupled receptor for a variety of signaling processes like hormonal signaling, and small G proteins are involved in processes like cellular trafficking and cell cycling. GAP's role in this function is to turn the G protein's activity off. In this sense, GAPs function is opposite to that of guanine nucleotide exchange factors (GEFs), which serve to enhance G protein signaling.

KRAS

The KRAS gene provides instructions for making a protein called K-Ras, part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). The K-Ras protein is a GTPase, which means it converts a molecule called GTP into another molecule called GDP. In this way the K-Ras protein acts like a switch that is turned on and off by the GTP and GDP molecules. To transmit signals, it must be turned on by attaching (binding) to a molecule of GTP. The K-Ras protein is turned off (inactivated) when it converts the GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell's nucleus. It is called KRAS because it was first identified as an oncogene in KirstenRAt Sarcoma virus. The viral oncogene was derived from cellular genome. Thus, KRAS gene in cellular genome is called a proto-oncogene.

Cyclin D1 Protein-coding gene in Homo sapiens

Cyclin D1 is a protein that in humans is encoded by the CCND1 gene.

Transforming protein RhoA Protein-coding gene in the species Homo sapiens

Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the RHOA gene. While the effects of RhoA activity are not all well known, it is primarily associated with cytoskeleton regulation, mostly actin stress fibers formation and actomyosin contractility. It acts upon several effectors. Among them, ROCK1 and DIAPH1 are the best described. RhoA, and the other Rho GTPases, are part of a larger family of related proteins known as the Ras superfamily, a family of proteins involved in the regulation and timing of cell division. RhoA is one of the oldest Rho GTPases, with homologues present in the genomes since 1.5 billion years. As a consequence, RhoA is somehow involved in many cellular processes which emerged throughout evolution. RhoA specifically is regarded as a prominent regulatory factor in other functions such as the regulation of cytoskeletal dynamics, transcription, cell cycle progression and cell transformation.

RASSF1

Ras association domain-containing protein 1 is a protein that in humans is encoded by the RASSF1 gene.

RAC3

Ras-related C3 botulinum toxin substrate 3 (Rac3) is a G protein that in humans is encoded by the RAC3 gene. It is an important component of intracellular signalling pathways. Rac3 is a member of the Rac subfamily of the Rho family of small G proteins. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases.

RhoC

RhoC is a small signaling G protein, and is a member of the Rac subfamily of the family Rho family of GTPases. It is encoded by the gene RHOC.

RASSF5

Ras association domain-containing protein 5 is a protein that in humans is encoded by the RASSF5 or F5 gene.

H19 (gene) Negative regulation (or limiting) of body weight and cell proliferation

H19 is a gene for a long noncoding RNA, found in humans and elsewhere. H19 has a role in the negative regulation of body weight and cell proliferation. This gene also has a role in the formation of some cancers and in the regulation of gene expression. .

DLC1

Deleted in Liver Cancer 1 also known as DLC1 and StAR-related lipid transfer protein 12 (STARD12) is a protein which in humans is encoded by the DLC1 gene.

ARHGDIB

Rho GDP-dissociation inhibitor 2 is a protein that in humans is encoded by the ARHGDIB gene. Aliases of this gene include RhoGDI2, GDID4, Rho GDI 2, and others.

LATS1

Large tumor suppressor kinase 1 (LATS1) is an enzyme that in humans is encoded by the LATS1 gene.

ID4 Protein-coding gene in humans

ID4 is a protein coding gene. In humans, it encodes for the protein known as DNA-binding protein inhibitor ID-4. This protein is known to be involved in the regulation of many cellular processes during both prenatal development and tumorigenesis. This is inclusive of embryonic cellular growth, senescence, cellular differentiation, apoptosis, and as an oncogene in angiogenesis.

CDKN2A

CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family member p16 and p14arf. Both act as tumor suppressors by regulating the cell cycle. p16 inhibits cyclin dependent kinases 4 and 6 and thereby activates the retinoblastoma (Rb) family of proteins, which block traversal from G1 to S-phase. p14ARF activates the p53 tumor suppressor. Somatic mutations of CDKN2A are common in the majority of human cancers, with estimates that CDKN2A is the second most commonly inactivated gene in cancer after p53. Germline mutations of CDKN2A are associated with familial melanoma, glioblastoma and pancreatic cancer. The CDKN2A gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

A metastasis suppressor is a protein that acts to slow or prevent metastases from spreading in the body of an organism with cancer. Metastasis is one of the most lethal cancer processes. This process is responsible for about ninety percent of human cancer deaths. Proteins that act to slow or prevent metastases are different from those that act to suppress tumor growth. Genes for about a dozen such proteins are known in humans and other animals.

PTPRG

Receptor-type tyrosine-protein phosphatase gamma is an enzyme that in humans is encoded by the PTPRG gene.

EMP3 Protein-coding gene in the species Homo sapiens

Epithelial membrane protein 3 (EMP3) is a trans-membrane signaling molecule that is encoded by the myelin-related gene EMP3. EMP3 is a member of the peripheral myelin protein gene family 22-kDa (PMP22), which is mainly responsible for the formation of the sheath of compact myelin. Although the detailed functions and mechanisms of EMP3 still remain unclear, it is suggested that EMP3 is possibly epigenetically linked to certain carcinomas.

mir-137

In molecular biology, miR-137 is a short non-coding RNA molecule that functions to regulate the expression levels of other genes by various mechanisms. miR-137 is located on human chromosome 1p22 and has been implicated to act as a tumor suppressor in several cancer types including colorectal cancer, squamous cell carcinoma and melanoma via cell cycle control.

Augurin

Augurin is a protein that in humans is encoded by the C2orf40 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000162595 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 "Entrez Gene: DIRAS family, GTP-binding RAS-like 3".
  4. 1 2 Yang J, Hu A, Wang L, Li B, Chen Y, Zhao W, Xu W, Li T (Jun 2009). "NOEY2 mutations in primary breast cancers and breast hyperplasia". Breast. 18 (3): 197–203. doi: 10.1016/j.breast.2009.04.004 . PMID   19482475.
  5. 1 2 3 4 5 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". Cancer Research. 63 (14): 4174–80. PMID   12874023.
  6. 1 2 3 Luo RZ, Fang X, Marquez R, Liu SY, Mills GB, Liao WS, Yu Y, Bast RC (May 2003). "ARHI is a Ras-related small G-protein with a novel N-terminal extension that inhibits growth of ovarian and breast cancers". Oncogene. 22 (19): 2897–909. doi: 10.1038/sj.onc.1206380 . PMID   12771940.
  7. 1 2 3 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). "NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas". Proceedings of the National Academy of Sciences of the United States of America. 96 (1): 214–9. doi: 10.1073/pnas.96.1.214 . PMC   15119 . PMID   9874798.
  8. ↑ 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". Biology of the Cell. 105 (2): 91–107. doi:10.1111/boc.201200030. PMID   23157514. S2CID   19790001.

Further reading

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