Inzulín - transkripce genu
The endogenous production of insulin is regulated in several steps along the synthesis pathway:
- Transcription from the insulin gene
- In mRNA stability
- The mRNA translation
- Posttranslational modifications [14]
Regulace transkripce - genové exprese
- Insulin accumulates in the presence of nutrients
- Decreases in response to nutrient deprivation [14]
- Discrete sequence elements within the promoter region of insulin gene
- A, C, E, Z, and CRE elements
- Determine localization of insulin in ß-cells
- Serve as binding sites for several ß-cell transcription factors to regulate insulin gene expression [14]
Insulin enhancer sequences - the A, C, and E elements
A elements
- Multiple A/T rich elements
- In the conserved control region of the insulin gene
- TAAT core in each of these A elements
- Central DNA binding recognition motif for homeodomain proteins
- Duodenal homeobox-1(PDX-1)
- Predominant binding factor
- Expression of PDX-1 in adult pancreas is generally restricted to islet ß-cells [14]
- Cdx2/3
- Cdx2/3 mutant mice have defects in only intestinal function [14]
- Isl-1
- In all types of islet cells
- Can activate somatostatin, glucagon, IAPP gene expression
- Islet formation during embryo development [14]
C element
- C1 element
- Rat insulin promoter element 3b (RIPE3b)1 and RIPE3b2
- Two factors that form protein-DNA complexes within the C1 element
- RIPE3b2
- Does not contribute to ß-cell-specific expression of the insulin gene
- Present in a variety of other tissues [14]
- RIPE3b1
- Binds MafA, which is expressed exclusively in ß-cells
- MafA also mediates glucose-regulated and fatty acid-inhibited insulin expression
- Prolonged exposure to FFA and high glucose inhibits insulin gene transcription by impairing nuclear cellular expression of MafA
- MafA deficient animals
- no defects in ß-cell development
- Impaired insulin expression in adult islets [14]
- C2 element = pancreatic islet cell enhancer sequence (PISCES)
- Contribute to insulin, glucagon, and somatostatin transcription
- Binding site for PAX6 in insulin and glucagon genes
- PAX6 contains a paired box bipartite DNA binding domain
- Required for normal transcription of insulin and islet development [14]
- PAX4 can bind to PISCES, absent in adult ß-cells
- Suppress PAX6-induced trans-activation [14]
E element
- (5'-GCCATCTG-3')
- Two separated mini-enhancer units within the insulin enhancer
- Rodents have two E elements , other mammals have only one
- Also found in the heavy-chain immunoglobulin and muscle creatine kinase control elements
- Can bind a number of transcriptional factors required in cell type determination:
- Muscle determination proteins MyoD
- Myf-5
- Myogenin [14]
- Activators include:
- BETA2/NeuroD1
- Enriched in islets
- Important in regulating insulin gene expression and ß-cell survival
- Pancreas-specific deficiency of BETA2/NeuroD in mice causes massive ß-cell apoptosis and subsequent diabetes and early death --E2/5 [14]
- E12
- E47 [14]
Z element
- Unique to human insulin
- Glucose-sensitive DNA-binding complex
- Transcriptional repressor in transformed ß-cell lines and primary fibroblast cells
- A element activation depends on the present of the Z element
- PDX-1 and MafA regulate insulin gene transcription through activation of the Z element [14]
Cyclic AMP response element (CRE)
- Gene promoter
- CRE1-4
- Variety of transcription factors
Regulační mechanismy mohou být druhově specifické.
