Protein pigeon homolog

<h2 id="gene">Gene</h2>
<p>The human <i>PION</i> gene is located on the long (q) arm of <a href="/facts/Chromosome_7_(human)/JsnLmfhe">chromosome 7</a> at band 11.23, from <a href="/facts/Base_pair/xmPpPQ9W">base pair</a> 76,778,007 to base pair 76,883,653.<a class="footnote-ref" id="fnref:2" href="#fn:2"><sup>2</sup></a> Highly conserved <i>PION</i> <a href="/facts/Homology_(biology)/muctKlyT">orthologs</a> have been identified in most <a href="/facts/Vertebrates/tT54FSTT">vertebrates</a> for which complete genome data are available.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a>  More distantly related orthologs are also expressed in insects including the <i>pigeon</i> gene in <i><a href="/facts/Drosophila_melanogaster/KtnHVCcB">Drosophila melanogaster</a></i> that when mutated produces the "pigeon" <a href="/facts/Phenotype/vxWXKGLj">phenotype</a>. The name of the human <i>PION</i> gene derives the corresponding <i>Drosophila</i> gene.
</p>
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<h2 id="protein">Protein</h2>
<p>The transcribed human pigeon homolog protein is 854 <a href="/facts/Amino_acid/WDxYwBny">amino acid</a> residues in length.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> A 16 k<a href="/facts/Atomic_mass_unit/IMATU3vf">Da</a> fragment (GSAP-16K) derived from 121 residues from the <a href="/facts/C-terminus/ws4scHgT">C-terminus</a> region of the full length protein is known as the γ-secretase activating protein (GSAP).<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a>
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<h2 id="function">Function</h2>
<p>γ-secretase activating protein (GSAP) increases <a href="/facts/Beta_amyloid/QkXy91f9">β-amyloid</a> production through a mechanism involving its interactions with both <a href="/facts/Gamma_secretase/knLshqIz">γ-secretase</a> and its substrate, the <a href="/facts/Amyloid_precursor_protein/38Gr9gMs">amyloid precursor protein</a> (APP).<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a>  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.
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<h2 id="therapeutic-target-for-alzheimers-disease">Therapeutic target for Alzheimer's disease</h2>
<p>The activating function of GSAP can be inhibited by the anticancer drug <a href="/facts/Imatinib/PSpRplHy">imatinib</a> (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<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> 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 <a href="/facts/Alzheimer%27s_disease/w7Ad6tdg">Alzheimer's disease</a> (AD).<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a>
</p><p>The drug <a href="/facts/Semagacestat/ME5FVMPD">semagacestat</a> 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.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a>  The failure of semagacestat to improve the <a href="/facts/Cognition/ga0tSBul">cognitive function</a> 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.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a>
</p>
<h2 id="discovery">Discovery</h2>
<p>The <i>PION</i> gene was originally discovered through a large scale <a href="/facts/Full_genome_sequencing/WNuHaU2K">genome sequencing</a> effort.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> However the function of the <i>PION</i> gene product remained a mystery. In the laboratory of <a href="/facts/Paul_Greengard/rTFYolrX">Paul Greengard</a>, a screen of compounds that could inhibit the formation of β-amyloid identified imatinib,<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> 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.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a>
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<h2 id="further-reading">Further reading</h2>

<ul><li>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 (December 2005). "Transcriptome analysis of human gastric cancer". <i>Mammalian Genome</i>. 16 (12): 942–54. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1007%2Fs00335-005-0075-2">10.1007/s00335-005-0075-2</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/16341674">16341674</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:69278">69278</a>.</li></ul>

<h2 id="references">References</h2>

<ol>
<li id="fn:1"><p>"Entrez Gene: pigeon homolog (Drosophila)". <a href="https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54103" target="_blank">https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54103</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li>
<li id="fn:2"><p>"Human chr7:76778007-76883653". UCSC Genome Browser. <a href="http://genome.ucsc.edu/cgi-bin/hgTracks?&hgt.out1=1.5x&position=chr7%3A76778007-76883653" target="_blank">http://genome.ucsc.edu/cgi-bin/hgTracks?&hgt.out1=1.5x&position=chr7%3A76778007-76883653</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li>
<li id="fn:3"><p>HomoloGene: 45504 <a href="/wiki/HomoloGene" target="_blank">/wiki/HomoloGene</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li>
<li id="fn:4"><p>UniProt: A4D1B5 <a href="/wiki/UniProt" target="_blank">/wiki/UniProt</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li>
<li id="fn:5"><p>He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P (September 2010). "Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease". Nature. 467 (7311): 95–8. Bibcode:2010Natur.467...95H. doi:10.1038/nature09325. PMC 2936959. PMID 20811458.
Gina Kolata (September 1, 2010). "Finding Suggests New Aim for Alzheimer's Drugs". The New York Times.
 <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936959" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936959</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li>
<li id="fn:6"><p>He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P (September 2010). "Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease". Nature. 467 (7311): 95–8. Bibcode:2010Natur.467...95H. doi:10.1038/nature09325. PMC 2936959. PMID 20811458.
Gina Kolata (September 1, 2010). "Finding Suggests New Aim for Alzheimer's Drugs". The New York Times.
 <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936959" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936959</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li>
<li id="fn:7"><p>Dai H, Marbach P, Lemaire M, Hayes M, Elmquist WF (March 2003). "Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux". The Journal of Pharmacology and Experimental Therapeutics. 304 (3): 1085–92. doi:10.1124/jpet.102.045260. PMID 12604685. S2CID 15871348. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li>
<li id="fn:8"><p>He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P (September 2010). "Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease". Nature. 467 (7311): 95–8. Bibcode:2010Natur.467...95H. doi:10.1038/nature09325. PMC 2936959. PMID 20811458.
Gina Kolata (September 1, 2010). "Finding Suggests New Aim for Alzheimer's Drugs". The New York Times.
 <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936959" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936959</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li>
<li id="fn:9"><p>St George-Hyslop P, Schmitt-Ulms G (September 2010). "Alzheimer's disease: Selectively tuning gamma-secretase". Nature. 467 (7311): 36–7. Bibcode:2010Natur.467...36S. doi:10.1038/467036a. PMID 20811445. S2CID 13792782. <a href="https://doi.org/10.1038%2F467036a" target="_blank">https://doi.org/10.1038%2F467036a</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li>
<li id="fn:10"><p>He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P (September 2010). "Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease". Nature. 467 (7311): 95–8. Bibcode:2010Natur.467...95H. doi:10.1038/nature09325. PMC 2936959. PMID 20811458.
Gina Kolata (September 1, 2010). "Finding Suggests New Aim for Alzheimer's Drugs". The New York Times.
 <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936959" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936959</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li>
<li id="fn:11"><p>Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, et al. (December 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC139241" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC139241</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li>
<li id="fn:12"><p>Netzer WJ, Dou F, Cai D, Veach D, Jean S, Li Y, Bornmann WG, Clarkson B, Xu H, Greengard P (October 2003). "Gleevec inhibits beta-amyloid production but not Notch cleavage". Proceedings of the National Academy of Sciences of the United States of America. 100 (21): 12444–9. Bibcode:2003PNAS..10012444N. doi:10.1073/pnas.1534745100. PMC 218777. PMID 14523244. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC218777" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC218777</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li>
<li id="fn:13"><p>He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P (September 2010). "Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease". Nature. 467 (7311): 95–8. Bibcode:2010Natur.467...95H. doi:10.1038/nature09325. PMC 2936959. PMID 20811458.
Gina Kolata (September 1, 2010). "Finding Suggests New Aim for Alzheimer's Drugs". The New York Times.
 <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936959" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936959</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li>
</ol>

Protein pigeon homolog open-in-new

Protein pigeon homolog