title: Functional role of an islet transcription factor, INSM1/IA-1, on pancreatic acinar cell trans-differentiation.
abstract: In this study, the functional role of INSM1 is examined with an AR42J acinar cell model for trans-differentiation into insulin-positive cells. Islet transcription factors (ITFs: INSM1, Pdx-1, and NeuroD1) are over-expressed in AR42J cells using adenoviral vectors. Addition of Ad-INSM1 alone or the combination of three ITFs to the AR42J cells triggers cellular trans-differentiation. Ectopic expression of INSM1 directly induces insulin, Pax6, and Nkx6.1 expression, whereas Pdx-1 and NeuroD1 were slightly suppressed by INSM1. Addition of Pdx-1 and NeuroD1 with INSM1 further enhances endocrine trans-differentiation by increasing both the numbers and intensity of the insulin-positive cells with simultaneous activation of ITFs, Ngn3 and MafA. INSM1 expression alone partially inhibits dexamethasone-induced exocrine amylase expression. The combination of the three ITFs completely inhibits amylase expression and concomitantly induces greater acinar cell trans-differentiation into endocrine cells. Also, addition of the three ITFs promotes EGF and TGFβ receptors expression. Stimulation by the three ITFs along with the EGF/TGFβ growth factors strongly promotes insulin gene expression. The combination of the three ITFs and EGF/TGFβ growth factors with the primary cultured pancreatic acini also facilitates exocrine to endocrine cell differentiation. Taken together, both the AR42J cell line and the primary cultured mouse acinar cells support INSM1 induced acini trans-differentiation model.
authors.affiliation: The Research Institute for Children, Children's Hospital, New Orleans, Louisiana, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Nicolle A
authors.initials: NA
authors.lastname: Saunee
authors.forename: Mary B
authors.initials: MB
authors.lastname: Breslin
authors.forename: Kejing
authors.initials: K
authors.lastname: Song
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lan
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000256:Adenoviridae / Q000235:genetics; D000681:Amylases / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation / Q000187:drug effects; D006224:Cricetinae; D003907:Dexamethasone / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D000681:Amylases; D051792:Basic Helix-Loop-Helix Proteins; D003907:Dexamethasone; D066246:ErbB Receptors; D005136:Eye Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D012097:Repressor Proteins; D015534:Trans-Activators; C094696:Klrg1 protein, rat; C498696:Neurog3 protein, rat; C491327:Nkx6-1 protein, rat; C000605730:PAX6 protein, human; C000605732:Pax6 protein, mouse; C000605733:Pax6 protein, rat; C084010:pancreatic and duodenal homeobox 1 protein; C087342:INSM1 protein, human; C093564:Neurogenic differentiation factor 1; C483803:Egfr protein, rat