PMID:10802714

Citation	Ferber, S, Halkin, A, Cohen, H, Ber, I, Einav, Y, Goldberg, I, Barshack, I, Seijffers, R, Kopolovic, J, Kaiser, N and Karasik, A (2000) Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat. Med. 6:568-72
Abstract	Insulin gene expression is restricted to islet beta cells of the mammalian pancreas through specific control mechanisms mediated in part by specific transcription factors. The protein encoded by the pancreatic and duodenal homeobox gene 1 (PDX-1) is central in regulating pancreatic development and islet cell function. PDX-1 regulates insulin gene expression and is involved in islet cell-specific expression of various genes. Involvement of PDX-1 in islet-cell differentiation and function has been demonstrated mainly by 'loss-of-function' studies. We used a 'gain-of-function' approach to test whether PDX-1 could endow a non-islet tissue with pancreatic beta-cell characteristics in vivo. Recombinant-adenovirus-mediated gene transfer of PDX-1 to the livers of BALB/C and C57BL/6 mice activated expression of the endogenous, otherwise silent, genes for mouse insulin 1 and 2 and prohormone convertase 1/3 (PC 1/3). Expression of PDX-1 resulted in a substantial increase in hepatic immunoreactive insulin content and an increase of 300% in plasma immunoreactive insulin levels, compared with that in mice treated with control adenovirus. Hepatic immunoreactive insulin induced by PDX-1 was processed to mature mouse insulin 1 and 2 and was biologically active; it ameliorated hyperglycemia in diabetic mice treated with streptozotocin. These data indicate the capacity of PDX-1 to reprogram extrapancreatic tissue towards a beta-cell phenotype, may provide a valuable approach for generating 'self' surrogate beta cells, suitable for replacing impaired islet-cell function in diabetics.
Links	PubMed Online version:10.1038/75050
Keywords	Adenoviridae/genetics; Animals; Aspartic Acid Endopeptidases/analysis; Duodenum; Gene Therapy/methods; Genes, Homeobox; Homeodomain Proteins; Hyperglycemia/chemically induced; Hyperglycemia/therapy; Insulin/blood; Islets of Langerhans; Liver/metabolism; Mice; Mice, Inbred C57BL; Proprotein Convertases; Streptozocin/pharmacology; Trans-Activators/therapeutic use
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:PDX1		GO:0010468: regulation of gene expression	ECO:0000315:		P		Fig 1 shows that the mice with the AdCMV-PDX-1 gene (in lanes 2-8), all show insulin production, whereas the control groups do not.	complete CACAO 5211
RAT:PDX1	involved_in	GO:0010468: regulation of gene expression	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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