Transcriptional factor paired box 6 (PAX6) is very important for the development of the eyes, central nervous system, and pancreas. PAX6 mutations are associated with a diabetic phenotype and abnormal glucose metabolism. Our previous study showed that PAX6 directly bound to and activated the prohormone convertase 1/3 (Pc1/3) gene promoter and subsequently regulated proinsulin processing. Prohormone convertase 2 (PC2) is the essential enzyme for pancreatic proinsulin processing. To study the regulation of PAX6 in Pc2 expression, we did research on the pancreas of Pax6 R266Stop mutant mice, where truncated mutations happened in the C-terminal of the PAX6 protein. Our studies showed that the mutant PAX6 protein was stable and regulated the activity of Pc2 promoter as shown by luciferase activity assays. We found that the wild-type PAX6 protein imparts a transcriptional effect, and the mutant PAX6 can also regulate the downstream molecules. The results provide new insights into the mechanism of truncated PAX6 in regulating the functions of the pancreas and endocrine system.
MishraRGorlovIPChaoLYSinghSSaundersGF. PAX6, paired domain influences sequence recognition by the homeodomain. J Biol Chem2002; 277: 49488–94.
2.
MansouriAHallonetMGrussP. Pax genes and their roles in cell differentiation and development. Curr Opin Cell Biol1996; 8: 851–7.
3.
KozmikZCzernyTBusslingerM. Alternatively spliced insertions in the paired domain restrict the DNA sequence specificity of Pax6 and Pax8. EMBO J1997; 16: 6793–803.
4.
SisodiyaSMFreeSLWilliamsonKAMitchellTNWillisCStevensJMKendallBEShorvonSDHansonIMMooreATHeyningenVv. PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans. Nat Genet2001; 28: 214–16.
5.
SimpsonTIPriceDJ. Pax6; a pleiotropic player in development. Bioessays2002; 24: 1041–51.
6.
YasudaTKajimotoYFujitaniYWatadaHYamamotoSWataraiTUmayaharaYMatsuhisaMGorogawaSiKuwayamaYTanoYYamasakiYHoriM. PAX6 mutation as a genetic factor common to aniridia and glucose intolerance. Diabetes2002; 51: 224–30.
7.
GrzeskowiakRAminJOetjenEKnepelW. Insulin responsiveness of the glucagon gene conferred by interactions between proximal promoter and more distal enhancer-like elements involving the paired-domain transcription factor Pax6. J Biol Chem2000; 275: 30037–45.
8.
NollM. Evolution and role of Pax genes. Curr Opin Genet Dev1993; 3: 595–605.
9.
GlaserTWaltonDSMaasRL. Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene. Nat Genet1992; 2: 232–9.
10.
JordanTHansonIZaletayevDHodgsonSProsserJSeawrightAHastieNHeyningenVv. The human PAX6 gene is mutated in two patients with aniridia. Nat Genet1992; 1: 328–32.
11.
LyonsLAMarthaAMintz-HittnerHASaundersGFFerrellRE. Resolution of the two loci for autosomal dominant aniridia, AN1 and AN2, to a single locus on chromosome11p13. Genomics1992; 13: 925–30.
12.
HansonIMSeawrightAHardmanKHodgsonSZaletayevDFeketeGHeyningenVv. PAX6 mutations in aniridia. Hum Mol Genet1993; 2: 915–20.
13.
DavisACowellJK. Mutations in the PAX6 gene in patients with hereditary aniridia. Hum Mol Genet1994; 2: 2093–7.
14.
MarthaAFerrellREMintz-HittnerHLyonsLASaundersGF. Paired box mutations in familial and sporadic aniridia predicts truncated aniridia proteins. Am J Hum Genet1994; 54: 801–11.
15.
MarthaADFerrellRESaundersGF. Nonsense mutation in the homeobox region of the aniridia gene. Hum Mutat1994; 3: 297–300.
16.
HillREFavorJHoganBLMTonCCTSaundersGFHansonIMProsserJJordanTHastieNDHeyningenVv. Mouse small eye results from mutations in a paired-like homeobox-containing gene. Nature1991; 354: 522–5.
17.
MatsuoTOsumi-YamashitaNNojiSOhuchiHKoyamaEMyokaiFMatsuoNTaniguchiSDoiHIsekiSNinomiyaYFujiwaraMWatanabeTEtoK. A mutation in the Pax-6 gene in rat small eye is associated with impaired migration of midbrain crest cells. Nat Genet1993; 3: 299–304.
18.
TonCCTHirvonenHMiwaHWeilMMMonaghanPJordanTHeyningenVvHastieNDMeijers-HeijboerHDrechslerMRoyer-PokoraBCollinsFSwaroopAStrongLCSaundersGF. Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region. Cell1991; 67: 1059–74.
19.
QuiringRWalldorfUKloterUGehringW. Homology of the eyeless gene of Drosophila to the small eye gene in mice and aniridia in humans. Science1994; 265: 785–9.
20.
CallaertsPHalderGGehringWJ. PAX-6 in development and evolution. Annu Rev Neurosci1997; 20: 483–523.
GlaserTWaltonDSCaiJEpsteinJAJepealLMaasRLPAX6 gene mutations in aniridia. In: WiggsJL (eds). Molecular Genetics of Ocular Disease, New York: Wiley-Liss, 1995.
23.
SinghSTangHKLeeJYSaundersGF. Truncation mutations in the transactivation region of PAX6 result in dominant-negative mutants. J Biol Chem1998; 273: 21531–41.
24.
WenJHChenYYSongSJDingJGaoYHuQKFengRPLiuYZRenGCZhangCYHongTPGaoXLiLS. Paired box 6 (PAX6) regulates glucose metabolism via proinsulin processing mediated by prohormone convertase 1/3 (PC1/3). Diabetologia2009; 52: 504–13.
25.
SmeekensSPMontagAGThomasGRizoCACarrollRBenigMPhillipsLAMartinSOhagiSGardnerPSwiftHHSteinerDF. Proinsulin processing by the subtilisin-related proprotein convertases furin, PC2, and PC3. Proc Natl Acad Sci1992; 89: 8822–6..
26.
MalideDSeidahNGChrétienMBendayanM. Electron microscopic immunocytochemical evidence for the involvement of the convertases PC1 and PC2 in the processing of proinsulin in pancreatic beta-cells. J Histochem Cytochem1995; 43: 311–19.
27.
HamaguchiKGaskinsHRLeiterEH. NIT-1, a pancreatic beta-cell line established from a transgenic NOD/Lt mouse. Diabetes1991; 40: 842–9.
28.
ClarkJDGebhartGFGonderJCKeelingMEKohnDF. Special report: the 1996 guide for the care and use of laboratory animals. ILAR J1997; 38: 41–8.
29.
HoriHGuYJNagataNBalamuruganANSatakeAMorimotoYWangWJMisawaYNozawaYNembaiTMiyamotoMNozawaMInoueK. Isolation, culture, and characterization of endocrine cells from 6-month-old porcine pancreas. Cell Transplant2001; 10: 459–64.
30.
MarzbanLSoukhatchevaGVerchereCB. Role of carboxypeptidase E in processing of pro-islet amyloid polypeptide in β-cells. Endocrinology2005; 146: 1808–17.
31.
MinJZWeiXLeYJieZJLinLShengLLGuangWS. Effects of cyclosporin A on gene expression profiles of NIT-1 pancreatic β-cell line. J First Mil Med Univ2005; 25: 853–7.
32.
SongSLiuYCongRZhangXYangZLiL. PAX6 mutation caused brain abnormalities in humans. Beijing Da Xue Xue Bao2005; 37: 48–50.
33.
TangHKSinghSSaundersGF. Dissection of the transactivation function of the transcription factor encoded by the eye developmental gene PAX6. J Biol Chem1998; 273: 7210–21.
34.
KatzLSGosmainYMarthinetEPhilippeJ. Pax6 regulates the proglucagon processing enzyme PC2 and its chaperone 7B2. Mol Cell Biol2009; 29: 2322–34.
35.
DingJGaoYZhaoJYanHGuoSYZhangQXLiLSGaoX. Pax6 haploinsufficiency causes abnormal metabolic homeostasis by downregulating glucagon-like peptide 1 in mice. Endocrinology2009; 150: 2136–44.
