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词条 Protein pigeon homolog
释义

  1. Gene

  2. Protein

  3. Function

  4. Therapeutic target for Alzheimer's disease

  5. Discovery

  6. References

  7. Further reading

{{Infobox_gene}}{{redirect|PION||Pion (disambiguation)}}Protein pigeon homolog also known as gamma-secretase activating protein (GSAP) is a protein that in humans is encoded by the PION gene.[1]

Gene

The human PION gene is located on the long (q) arm of chromosome 7 at band 11.23, from base pair 76,778,007 to base pair 76,883,653.[2] Highly conserved PION orthologs have been identified in most vertebrates for which complete genome data are available.[3] More distantly related orthologs are also expressed in insects including the pigeon gene in Drosophila melanogaster that when mutated produces the "pigeon" phenotype. The name of the human PION gene derives the corresponding Drosophila gene.

{{Infobox nonhuman protein Name = pigeon image = width = caption = Organism = Drosophila melanogaster TaxID = 7227 Symbol = Pigeon AltSymbols = Protein linotte IUPHAR_id = ATC_prefix = ATC_suffix = ATC_supplemental = CAS_number = CAS_supplemental = DrugBank = EntrezGene = 35200 PDB = RefSeqmRNA = NM_057598 RefSeqProtein = NP_476946 UniProt = Q24118 ECnumber = Chromosome = 2L EntrezChromosome = NT_033779 GenLoc_start = 19185455 GenLoc_end = 19190522
}}

Protein

The transcribed human pigeon homolog protein is 854 amino acid residues in length.[4] A 16 kDa fragment (GSAP-16K) derived from 121 residues from the C-terminus region of the full length protein is known as the γ-secretase activating protein (GSAP).[5]

Function

γ-secretase activating protein (GSAP) increases β-amyloid production through a mechanism involving its interactions with both γ-secretase and its substrate, the amyloid precursor protein (APP).[5] By binding to both the γ-secretase enzyme and its APP substrate, GSAP increases the affinity and the selectivity of the enzyme for this particular substrate.

Therapeutic target for Alzheimer's disease

The activating function of GSAP can be inhibited by the anticancer drug imatinib (Gleevec) which in turn prevents γ-secretase from converting APP into plaque forming β-amyloid without affecting the other functions of γ-secretase. Imatinib itself does not get into the brain[6] so imatinib could not be used as an AD therapeutic. However it may be possible to identify imatinib-like drugs that do get into the brain. Hence GSAP represents a potential therapeutic target for the treatment of Alzheimer's disease (AD).[5]

The drug semagacestat in contrast to imatinib, works by directly inhibiting the γ-secretase. While semagacestat reduces β-amyloid plaque formation in AD patients, γ-secretase is also needed to make other important proteins.[7] The failure of semagacestat to improve the cognitive function of AD patients may be due to its non-selective blockade of γ-secretase. The more selective blockade of γ-secretase provided by inhibiting GSAP may make GSAP a more efficacious and safer drug target than γ-secretase.[5]

Discovery

The PION gene was originally discovered through a large scale genome sequencing effort.[8] However the function of the PION gene product remained a mystery. In the laboratory of Paul Greengard, a screen of compounds that could inhibit the formation of β-amyloid identified imatinib,[9] however it was not immediately known how it accomplished this. Later it was discovered by Greengard's lab that imatinib inhibited the function of GSAP and that GSAP in turn functions as an activator of γ-secretase.[5]

References

1. ^{{cite web | title = Entrez Gene: pigeon homolog (Drosophila)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54103| accessdate = }}
2. ^{{cite web | url = http://genome.ucsc.edu/cgi-bin/hgTracks?&hgt.out1=1.5x&position=chr7%3A76778007-76883653 | title = Human chr7:76778007-76883653 | date = | format = | work = UCSC Genome Browser | publisher = | pages = | archiveurl = | archivedate = | quote = | accessdate = }}
3. ^{{Homologene|45504}}
4. ^UniProt: {{Uniprot|A4D1B5}}
5. ^1 2 3 4 {{cite journal | vauthors = He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P | title = Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease | journal = Nature | volume = 467 | issue = 7311 | pages = 95–8 | date = September 2010 | pmid = 20811458 | pmc = 2936959 | doi = 10.1038/nature09325 | laysummary = https://www.nytimes.com/2010/09/02/health/research/02alzheimer.html | laysource = New York Times }}
6. ^{{cite journal | vauthors = Dai H, Marbach P, Lemaire M, Hayes M, Elmquist WF | title = Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 304 | issue = 3 | pages = 1085–92 | date = March 2003 | pmid = 12604685 | doi = 10.1124/jpet.102.045260 }}
7. ^{{cite journal | vauthors = St George-Hyslop P, Schmitt-Ulms G | title = Alzheimer's disease: Selectively tuning gamma-secretase | journal = Nature | volume = 467 | issue = 7311 | pages = 36–7 | date = September 2010 | pmid = 20811445 | doi = 10.1038/467036a }}
8. ^{{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 | display-authors = 6 | 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 }}
9. ^{{cite journal | vauthors = Netzer WJ, Dou F, Cai D, Veach D, Jean S, Li Y, Bornmann WG, Clarkson B, Xu H, Greengard P | title = Gleevec inhibits beta-amyloid production but not Notch cleavage | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 21 | pages = 12444–9 | date = October 2003 | pmid = 14523244 | pmc = 218777 | doi = 10.1073/pnas.1534745100 }}

Further reading

{{refbegin}}
  • {{cite journal | vauthors = Oh JH, Yang JO, Hahn Y, Kim MR, Byun SS, Jeon YJ, Kim JM, Song KS, Noh SM, Kim S, Yoo HS, Kim YS, Kim NS | title = Transcriptome analysis of human gastric cancer | journal = Mammalian Genome | volume = 16 | issue = 12 | pages = 942–54 | date = December 2005 | pmid = 16341674 | doi = 10.1007/s00335-005-0075-2 }}
{{refend}}
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