Insulin gene
From Wikipedia, the free encyclopedia
The insulin gene (abbreviated INS[1]) is the gene coding for the hormone insulin.
It is mainly expressed in beta-cells in the pancreas, but also in the yolk sac, CNS, other endocrine cells in the pancreas and gastrointestinal tract and in the thymus.
Contents |
[edit] Mechanism
- Further information: Insulin#Structure_and_production
The insulin gene encodes the mRNA for pre-proinsulin. After removal of the precursor signal peptide, proinsulin is post-translationally cleaved into two chains (peptide A and peptide B) that are covalently linked via two disulfide bonds. Binding of this mature form of insulin to the insulin receptor (INSR) stimulates glucose uptake.
[edit] Alleles
A variety of mutant alleles with changes in the coding region have been identified. There is a read-through gene, INS-IGF2, which overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region.[2]
[edit] Regulation
There are several regulatory sequences in the promoter region of the human insulin gene, to which transcription factors bind.
In general, the A-boxes bind to Pdx1 factors, E-boxes bind to NeuroD, C-boxes bind to MafA and cAMP response elements to CREB.
There are also silencers that inhibit transcription.
[edit] Overview table
| Regulatory sequence | binding transcription factors |
|---|---|
| ILPR | Par1 |
| A5 | Pdx1 |
| negative regulatory element (NRE)[4] | glucocorticoid, Oct1 |
| Z (overlapping NRE and C2) | ISF |
| C2 | Pax4, MafA(?) |
| E2 | USF |
| A3 | Pdx1 |
| cAMP response element | - |
| cAMP response element | CREB, CREM |
| A2 | - |
| CAAT enhancer binding (CEB) (partly overlapping A2 and C1) | - |
| C1 | - |
| E1 | E2A, NeuroD1, HEB |
| A1 | Pdx1 |
| G1 | - |
[edit] By dietary intake
Glucose has both stimulatory and inhibitory effects on insulin gene transcription, while fatty acids act in an inhibitory way;
Glucose increases transcription by promoting A-box-Pdx1 and C-box-MafA. At the same time, however, it causes production of reactive oxygen species (ROS), which acts on MafA in an inhibitory way.[5] ROS also causes activation of C-Jun N-terminal kinases that inhibit NeuroD1.[5] In addition, fatty acids also inhibits transcription by, in fatty acid metabolism, creating ceramide, which inhibits Pdx1 and MafA.[5]
[edit] Mutations
Notable mutations are e.g. C65R (the cysteine (C) residue 65 is exchanged for an arginine (R)), wherein only proinsulin is generated.
Another is B10H, wherein the product is stuck in the endoplasmatic reticulum, causing ER stress and apoptosis of the beta cells.
[edit] References
- ^ genenames.org
- ^ Entrez Gene: INS insulin.
- ^ Melloul D, Marshak S, Cerasi E (2002). "Regulation of insulin gene transcription". Diabetologia 45 (3): 309–26. doi:. PMID 11914736.
- ^ Jang WG, Kim EJ, Park KG, Park YB, Choi HS, Kim HJ, Kim YD, Kim KS, Lee KU, Lee IK (2007). "Glucocorticoid receptor mediated repression of human insulin gene expression is regulated by PGC-1alpha". Biochem. Biophys. Res. Commun. 352 (3): 716–21. doi:. PMID 17150186.
- ^ a b c Nutrient regulation of the insulin gene. Poitut et al., Journal of nutrition, 136, 873-878, 2006
[edit] Further reading
- Goodge KA, Hutton JC (2000). "Translational regulation of proinsulin biosynthesis and proinsulin conversion in the pancreatic beta-cell.". Semin. Cell Dev. Biol. 11 (4): 235-42. doi:. PMID 10966857.
- Kino T, Chrousos GP (2004). "Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/lipodystrophy syndrome?". Ann. N. Y. Acad. Sci. 1024: 153-67. doi:. PMID 15265780.
- Marques RG, Fontaine MJ, Rogers J (2005). "C-peptide: much more than a byproduct of insulin biosynthesis.". Pancreas 29 (3): 231-8. PMID 15367890.
- Pugliese A (2006). "The insulin gene in type 1 diabetes.". IUBMB Life 57 (7): 463-8. doi:. PMID 16081366.
