Regulation of Human Insulin Receptor RNA Splicing in HepG2 Cells: Effects of Glucocorticoid and Low Glucose Concentration

Norgren, Svante; Li, Luo-Sheng; Luthman, Holger

doi:10.1006/bbrc.1994.1225

Cited by 39 publications

(22 citation statements)

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“…Data are then expressed for the three groups of type 2 diabetic patients and statistically compared (17)(18)(19). A separate set of experiments was repeated with a pool of RNA obtained from the three different groups and compared; these latter data are not shown, but they confirmed the data shown as mean values plus SD reported.…”

Section: Ctsupporting

confidence: 59%

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Altered Transcapillary Escape of Albumin and Microalbuminuria Reflects Two Different Pathogenetic Mechanisms

Nosadini

Velussi

Brocco³

et al. 2005

Diabetes

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We studied the following in normo-and microalbuminuric hypertensive type 2 diabetic patients: 1) transcapillary escape rate of albumin (TERalb) and 2) expression of mRNA slit diaphragm and podocyte proteins in renal biopsies. Normoalbuminuric subjects had renal cancer, and kidney biopsy was performed during surgery. TERalb was evaluated by clearance of 125 Ialbumin. Real-time PCR of mRNA slit diaphragm was measured in kidney specimens. Albumin excretion rate (AER) was by definition lower in normoalbuminuric subjects than in microalbuminuric subjects with typical diabetic glomerulopathy (group 1), in microalbuminuric subjects with normal or near-normal glomerular structure (group 2), and in microalbuminuric subjects with atypical diabetic nephropathy (group 3). This classification was based on light microscopy analysis of renal tissue. TERalb (%/h) was similar in normoalbuminuric and microalbuminuric group 1, 2, and 3 diabetic patients (medians: 14.1 vs. 14.4 vs. 15.7 vs. 14.9, respectively) (ANOVA, NS). mRNA expression of slit diaphragm proteins CD2AP, FAT, Actn 4, NPHS1, and NPHS2 was higher in normoalbuminuric patients than in microalbuminuric patients (groups 1, 2, and 3) (ANOVA, P < 0.001). All diabetic patients had greater carotid artery intimal thickness than normal control subjects using ultrasound technique (ANOVA, P < 0.01). In conclusion, the present study suggests that microalbuminuria identifies a subgroup of hypertensive type 2 diabetic patients who have altered mRNA expression of slit diaphragm and podocyte proteins, even before glomerular structure shows abnormalities using light microscopy analysis. (1) suggested some years ago an interesting view to understanding the pathogenesis of albuminuria in diabetes, which has been usually cited as the Steno hypothesis and implies that albuminuria reflects a widespread vascular damage due to a generalized vascular dysfunction in the overall vascular bed. According to this hypothesis, albuminuria may be a marker of generalized disease in the vascular wall, either at endothelial or glomerular basement membrane (GBM) levels or both, although the precise reasons for this relationship are not completely understood.If the Steno hypothesis really does account for both the leakage of albumin at kidney level and an increased transport of albumin across microvascular capillaries in the overall body, one should predict that transvascular and urinary leakage of albumin are correlated throughout a gamut of pathological conditions both in type 1 and type 2 diabetic patients.However, this is not the case in previous reports both in type 2 diabetic patients and in nondiabetic atherosclerotic and hypertensive patients, in whom transvascular escape of albumin was similarly abnormal in normoalbuminuric and micro-/macroalbuminuric patients (2,3).Major attention has been paid in the last 30 years to the role of the GBM as the primary filter capable of maintaining albumin and large proteins into circulation (4). Because GBM is widespread throughout the entire vascular bed of ...

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Section: Ctsupporting

confidence: 59%

“…The mean of three independent experiments was used. All PCR products were confirmed to be the expected cDNA by subcloning the PCR product using the PGEM-T vector system (Promega, Madison, WI, and Milan, Italy) and then sequencing the cloned fragments (17)(18)(19).…”

Section: Methodsmentioning

confidence: 99%

Altered Transcapillary Escape of Albumin and Microalbuminuria Reflects Two Different Pathogenetic Mechanisms

Nosadini

Velussi

Brocco³

et al. 2005

Diabetes

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“…In the embryo, the IR lacking exon 11 (IR-A) promotes growth due to its ability to bind both insulin and insulin-like growth factor II; in the adult, the IR containing exon 11 (IR-B) is expressed predominantly in the insulin-sensitive tissues comprising the liver, muscle, adipocytes, and kidney, which regulate glucose homeostasis, and binds only insulin. Inclusion of IR exon 11 is both developmentally and hormonally regulated and is altered in a number of disease states, such as type II diabetes, myotonic dystrophy, aging, and cancer (15,17,(27)(28)(29)33). The dysregulation of the alternative splicing of the IR may therefore have important consequences for insulin and insulin-like growth factor II sensitivity and responsiveness.…”

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confidence: 99%

SRp20 and CUG-BP1 Modulate Insulin Receptor Exon 11 Alternative Splicing

Sen

Talukdar

Webster

2009

Molecular and Cellular Biology

108

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The insulin receptor (IR) exists as two isoforms, IR-A and IR-B, which result from alternative splicing of exon 11 in the primary transcript. This alternative splicing is cell specific, and the relative proportions of exon 11 isoforms also vary during development, aging, and different disease states. We have previously demonstrated that both intron 10 and exon 11 contain regulatory sequences that affect IR splicing both positively and negatively. In this study, we sought to define the precise sequence elements within exon 11 that control exon recognition and cellular factors that recognize these elements. Using minigenes carrying linker-scanning mutations within exon 11, we detected both exonic splicing enhancer and exonic splicing silencer elements. We identified binding of SRp20 and SF2/ASF to the exonic enhancers and CUG-BP1 to the exonic silencer by RNA affinity chromatography. Overexpression and knockdown studies with hepatoma and embryonic kidney cells demonstrated that SRp20 and SF2/ASF increase exon inclusion but that CUG-BP1 causes exon skipping. We found that CUG-BP1 also binds to an additional intronic splicing silencer, located at the 3 end of intron 10, to promote exon 11 skipping. Thus, we propose that SRp20, SF2/ASF, and CUG-BP1 act antagonistically to regulate IR alternative splicing in vivo and that the relative ratios of SRp20 and SF2/ASF to CUG-BP1 in different cells determine the degree of exon inclusion.In mammals, alternative splicing is a common strategy for creating functional diversities of proteins that have cell and developmentally specific functions. Given the important role for splicing, it is not surprising that a recent estimate has proposed that 50 to 60% of mutations linked to disease affect splicing (21, 43). The majority of human genes undergo alternative pre-mRNA splicing through the use of competing 5Ј or 3Ј splice sites or through alternative inclusion/exclusion of exons in the pre-mRNA. These alternative exons often contain splice sites that diverge from the consensus site, and the presence of cis regulatory elements within the exon and/or the flanking introns determines whether these exons are recognized (18,20,31). These cis elements can have either a positive (enhancer) or a negative (silencer) effect on splicing. Both enhancers and silencers are thought to function through binding to specific trans-acting protein factors (1). Differences in the expression or activities of these trans-acting factors may modulate the recognition of the alternative exon and lead to developmental or tissue-specific differences in splicing. Proteins that bind to specific sequence elements to affect splice site selection include SR proteins, hnRNPs, and other related RNA binding proteins, such as the CELF family, TIA-1, and Raver-1 (11,12,14,25,32). Adding a further layer of regulation, local context, such as RNA secondary structure, may influence the way that binding motifs are recognized by their cognate factors (3, 10, 13).The human insulin receptor (IR) is encoded by a single INSR gene th...

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“…In vivo [104] and in vitro [105] studies conducted by Norgren et al revealed that alternative splicing of the insulin receptor transcript may be regulated hormonally and metabolically.…”

Section: Insulin Receptor Isoforms and Insr/igf-1r Hybrid Receptorsmentioning

confidence: 99%

Insulin Receptor and its Relationship with Different Forms of Insulin Resistance

Rojek¹,

Niedziela²

2010

Advances in Cell Biology

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Summary:Insulin plays an important role in maintaining the whole organism's homeostasis. The presence of insulin receptors in all vertebrates and invertebrates cells reflects the diversity of regulatory processes in which this hormone is involved. Furthermore, many different factors may influence the level of insulin receptor expression. These factors include e.g. the sole insulin or stage of development. Mutations in the receptor may lead to the development of insulin resistance. These mutations differ in the level of severity and are frequently associated with diabetes mellitus, hypertension, cardiovascular disorders, heart failure, metabolic syndrome and infertility in women. More than 50 mutations in insulin receptor gene have already been characterized. These mutations are associated with rare forms of insulin resistance like leprechaunism, insulin resistance type A or Rabson-Mendenhall syndrome. Molecular analysis of insulin receptor gene may lead to a better understanding of molecular mechanisms underlying various types of insulin resistance and help to develop more efficient treatment.

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Regulation of Human Insulin Receptor RNA Splicing in HepG2 Cells: Effects of Glucocorticoid and Low Glucose Concentration

Cited by 39 publications

References 0 publications

Altered Transcapillary Escape of Albumin and Microalbuminuria Reflects Two Different Pathogenetic Mechanisms

Altered Transcapillary Escape of Albumin and Microalbuminuria Reflects Two Different Pathogenetic Mechanisms

SRp20 and CUG-BP1 Modulate Insulin Receptor Exon 11 Alternative Splicing

Insulin Receptor and its Relationship with Different Forms of Insulin Resistance

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