1. Function

2. Discovery

3. Gene location of GAS1

4. GAS1 characteristic
     Gene structure  

5. Gene expression

6. Function
     Associated diseases    Kidney hypoplasia  

7. Gene mutation

8. References

9. Further reading

Function

Growth arrest-specific 1 plays a role in growth suppression. GAS1 blocks entry to S phase and prevents cycling of normal and transformed cells. Gas1 is a putative tumor suppressor gene.^[2]

Discovery

The mouse cells, which appear the growth-arrested, were observed  expression of Growth Arrest Specific-1 gene (GAS1)^[1]. In 1988, Gas-1 was first defined as one of six genes that block transcriptional up-regulation of the NIH3T3 cell cycle from G0 to S phase^[2]. Most of scientist have proved that overexpressed gas1 has the function of inhibiting tumor growth and progression in gliomas. Furthermore, GAS1 gene was also thought to contribute to recurrence and metastasized prediction in colon cancer.

Gene location of GAS1

GAS-1 gene has been identified as a putative tumor suppressor collocates on chromosome 9q21.3-22.1 where was considered to be a fragile site.^[3] In 1994, 29 metaphases were analyzed by Del Sal G et al, and 102 fluorescent signals were observed during the experiment. The results showed that 84 (82%) expression rate of the fluorescent signal on chromosome 9^[4]. Furthermore, the peak signal density of the fluorescent also observed occurring in the q21.3-22.1 region.^[4] In addition, the inexpression of the fluorescent signal cluster on any other chromosome further demonstrates Gas1 gene specifically expresses on chromosome 9q21.3-22.1.^[4]

GAS1 characteristic

345 amino acids were confirmed to constitute mature Gas-1 gene. Asn117 and an aminated Ser318 are two particular position which result in discovering of the one N-glycosylation site and potential signal peptide, respectively.^[5]

Gene structure

Gas-1 gene has been confirmed to be highly similar to the GFRα1 gene (28% similarity) while the Gas1 only consists of two domains which is different from the GFRα1-3 that composes of three domains.^[6][7] Although the structure of GAS1 gene is similar to GFRαs, the function of GAS1 is largely different from GFRαs since the GAS 1 gene has the ability of binding RET in a ligand independent manner ^[7][8]. Since the structure similarity between GAS1 and GFRαs, the ancestor of GFRα proteins was suspected to be the GAS1.^[8] In regard to the secondary structure, most of mammalian Gas1 gene’s secondary structure were identified to be mostly α-helical and to have a long unstructured C-terminal domain^[6]

Gene expression

GAS1 protein widespread distributed in adult mammalian CNS ( central nervous system). Adult mouse brain has been described expressing GAS1 mRNA, and the experiment of Natanael Zarco et al further corroborated this description.^[9] Western blot analysis is the main method which has been used in their practical and plays an significant role in successfully determining the distribution of the protein in the adult central nervous system (CNS).^[9] Olfactory bulb, caudate-putamen, cerebral cortex, hippocampus, mesencephalon, medulla oblongata, cerebellum, and cervical spinal cord has been identified as the  specific expression parts of GAS1.^[9] Despite the pattern of expression in Astrocyte cells was more limited than in neurons, the gas1 was also found expressing in that part.

Function

GAS1 was identified as a pleiotropic protein with the function of the cell arrest and apoptosis. Except that, the nervous system and other amount of organs can also be largely influenced by the abnormal Gas1 gene. The reason of this dual function is likely caused by its ability of interacting with the inhibited signaling cascade which induced by GNDF (glial cell-line derived neurotrophic factor)^[9]. Additionally, GAS1 has been proved can largely influence the developmental state of the organs.^[10] During the development stage of the GAS1, it has been suggested that development GAS1 can not only inhibit cell proliferation but also control the cell death as well as growth of the cerebellum.^[5] The signal emission of GAS 1 protein associate with two different types of transmembrane receptor protein, including RET and the Hedgehog receptor protein^[11], GAS1 is therefore determined as a kind of multifunctional protein. The Hedgehog signaling pathway is known as an essential part in the body which largely influences the body development, and cancer progression since the Sonic hedgehog can be connected by GAS1 directly, and lead to active of the signaling pathway.^[12]

Associated diseases

Kidney hypoplasia

The GAS1 gene plays a significant role in Kidney development. Conserved DNA binding motif, which is located in the Gas1 promoter, is directly bind by the WT1, and then the Gas1 mRNA is activated to transcript to the NPCs.^[13] The WT1 has been confirmed as a necessary part for expressing Gas1 in kidneys in vivo. Loss of function of GAS1 in vivo results in hypoplastic kidneys with reduced nephron mass due to premature depletion of NPCs.^[13] In humans, fetal period is the most significant time point for inducting a new nephrons, no matter what kind of mammals, once the NPCS disappeared, there is no possibility for inducing the new nephrons.^[13]

Gene mutation

Gas1 gene has been mapped by the method of in situ hybridization to human chromosome bands 9q21.3-q22^[4], a fragile site where frequently deleted in human tumors, especially acute myeloid leukemia and bladder tumors.^[14] The deletion region of early superficial bladder cancer indicated that the frequent (50%) deletion of tumor suppressor genes was located between 9q22 and 9p12-13, an area that spanned the GAS1 gene position and could be a starting event for bladder cancer disease.^[15] However, a study that has been done by Simoneau et al indicates that there is no mutations in the gas1 gene in 14 primary bladder carcinomas and 10 bladder carcinoma cell lines, which means the mutation of gas1 is not the main reason in causing the pathogenesis.

References

Further reading

• {{cite journal | vauthors = Del Sal G, Ruaro ME, Philipson L, Schneider C | title = The growth arrest-specific gene, gas1, is involved in growth suppression | journal = Cell | volume = 70 | issue = 4 | pages = 595–607 | date = August 1992 | pmid = 1505026 | doi = 10.1016/0092-8674(92)90429-G }}
• {{cite journal | vauthors = Wicking C, Breen M, Negus K, Berkman J, Evdokiou A, Cowled P, Chenevix-Trench G, Wainwright B | title = The human growth-arrest-specific gene GAS1 maps outside the candidate region of the gene for nevoid basal cell carcinoma syndrome | journal = Cytogenetics and Cell Genetics | volume = 68 | issue = 1-2 | pages = 119–21 | year = 1994 | pmid = 7956349 | doi = 10.1159/000133904 }}
• {{cite journal | vauthors = Del Sal G, Collavin L, Ruaro ME, Edomi P, Saccone S, Valle GD, Schneider C | title = Structure, function, and chromosome mapping of the growth-suppressing human homologue of the murine gas1 gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 5 | pages = 1848–52 | date = March 1994 | pmid = 8127893 | pmc = 43261 | doi = 10.1073/pnas.91.5.1848 }}
• {{cite journal | vauthors = Evdokiou A, Cowled PA | title = Tumor-suppressive activity of the growth arrest-specific gene GAS1 in human tumor cell lines | journal = International Journal of Cancer | volume = 75 | issue = 4 | pages = 568–77 | date = February 1998 | pmid = 9466658 | doi = 10.1002/(SICI)1097-0215(19980209)75:4<568::AID-IJC13>3.0.CO;2-5 }}
• {{cite journal | vauthors = Stebel M, Vatta P, Ruaro ME, Del Sal G, Parton RG, Schneider C | title = The growth suppressing gas1 product is a GPI-linked protein | journal = FEBS Letters | volume = 481 | issue = 2 | pages = 152–8 | date = September 2000 | pmid = 10996315 | doi = 10.1016/S0014-5793(00)02004-4 }}
• {{cite journal | vauthors = Lee CS, Buttitta L, Fan CM | title = Evidence that the WNT-inducible growth arrest-specific gene 1 encodes an antagonist of sonic hedgehog signaling in the somite | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 20 | pages = 11347–52 | date = September 2001 | pmid = 11572986 | pmc = 58732 | doi = 10.1073/pnas.201418298 }}
• {{cite journal | vauthors = Baladrón V, Ruiz-Hidalgo MJ, Bonvini E, Gubina E, Notario V, Laborda J | title = The EGF-like homeotic protein dlk affects cell growth and interacts with growth-modulating molecules in the yeast two-hybrid system | journal = Biochemical and Biophysical Research Communications | volume = 291 | issue = 2 | pages = 193–204 | date = February 2002 | pmid = 11846389 | doi = 10.1006/bbrc.2002.6431 }}
• {{cite journal | vauthors = Mellström B, Ceña V, Lamas M, Perales C, Gonzalez C, Naranjo JR | title = Gas1 is induced during and participates in excitotoxic neuronal death | journal = Molecular and Cellular Neurosciences | volume = 19 | issue = 3 | pages = 417–29 | date = March 2002 | pmid = 11906213 | doi = 10.1006/mcne.2001.1092 }}
• {{cite journal | vauthors = Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA | title = Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 26 | pages = 16899–903 | date = December 2002 | pmid = 12477932 | pmc = 139241 | doi = 10.1073/pnas.242603899 }}
• {{cite journal | vauthors = Xu Y, Kulkosky J, Acheampong E, Nunnari G, Sullivan J, Pomerantz RJ | title = HIV-1-mediated apoptosis of neuronal cells: Proximal molecular mechanisms of HIV-1-induced encephalopathy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 18 | pages = 7070–5 | date = May 2004 | pmid = 15103018 | pmc = 406467 | doi = 10.1073/pnas.0304859101 }}
• {{cite journal | vauthors = Cabrera JR, Sanchez-Pulido L, Rojas AM, Valencia A, Mañes S, Naranjo JR, Mellström B | title = Gas1 is related to the glial cell-derived neurotrophic factor family receptors alpha and regulates Ret signaling | journal = The Journal of Biological Chemistry | volume = 281 | issue = 20 | pages = 14330–9 | date = May 2006 | pmid = 16551639 | doi = 10.1074/jbc.M509572200 }}

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