title: Evolution of a potential hormone antagonist following gene splicing during primate evolution.
abstract: Alternative splicing of genes generates novel mRNAs, leading to the evolution of new functional proteins. Cholecystokinin (CCK) induces the release of pancreatic enzymes and the contraction of the gallbladder to promote the digestion of fat and proteins. CCK activates two G-protein-coupled receptors, CCKA and CCKB. Here, we showed that a CCKsv (splicing variant), originated de novo during Catarrhini evolution by including a portion of intronic sequence of the CCK gene, encodes novel C-terminal peptide sequence followed by a new poly-adenylation signal. CCKsv is expressed in many human tissues and likely a secreted peptide retaining the original signal peptide and the N-terminal proteolytic processing signal, together with novel C-terminal sequences. Although CCKsv cannot activate CCK receptors, it partially inhibits the CRE- or SRF-driven reporter activities stimulated by wide type CCK-8 mediated by both CCK receptors. Co-treatment with CCKsv also partially antagonizes Ewing tumor cell growth stimulated by CCK-8. Our study provides an example of new peptide hormone antagonist evolution in primates.
authors.affiliation: Program of Reproductive and Stem Cell Biology, Department of Obstetrics/Gynecology, Stanford University School of Medicine, Stanford, California, United States of America. cdeng@stanford.edu
authors.forename: Cheng
authors.initials: C
authors.lastname: Deng
authors.forename: Aaron J W
authors.initials: AJ
authors.lastname: Hsueh
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002766:Cholecystokinin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D006727:Hormone Antagonists / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007438:Introns / Q000235:genetics; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000235:genetics; D011323:Primates / Q000235:genetics*; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000473:pathology
chemical_list: D006727:Hormone Antagonists; D011949:Receptors, Cholecystokinin; D002766:Cholecystokinin