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A kinase-independent role for unoccupied insulin and IGF-1 receptors in the control of apoptosis.

ABSTRACT: Insulin and insulin-like growth factor 1 (IGF-1) act as antiapoptotic hormones. We found that, unexpectedly, double-knockout (DKO) cells that lacked both insulin and IGF-1 receptors (IR and IGF1R, respectively) were resistant to apoptosis induced through either the intrinsic or the extrinsic pathway. This resistance to apoptosis was associated with decreased abundance of the proapoptotic protein Bax and increases in abundance of the antiapoptotic proteins Bcl-2, Bcl-xL, XIAP, and Flip. These changes in protein abundance involved primarily posttranscriptional mechanisms. Restoration of IR or IGF1R to DKO cells also restored their sensitivity to apoptosis. Notably, expression of a catalytically inactive mutant form of the IR also restored susceptibility to apoptosis. Thus, IR and IGF1R have bidirectional roles in the control of cell survival and can be viewed as dependence receptors. Insulin and IGF-1 binding stimulates receptor tyrosine kinase activity and blocks apoptosis, whereas unliganded IR and IGF1R, acting through a mechanism independent of their catalytic activity, exert a permissive effect on cell death.

SUBMITTER: Boucher J

PROVIDER: S-EPMC4364396 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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A kinase-independent role for unoccupied insulin and IGF-1 receptors in the control of apoptosis.

Boucher Jeremie J Macotela Yazmin Y Bezy Olivier O Mori Marcelo A MA Kriauciunas Kristina K Kahn C Ronald CR

Science signaling 20101207 151

Insulin and insulin-like growth factor 1 (IGF-1) act as antiapoptotic hormones. We found that, unexpectedly, double-knockout (DKO) cells that lacked both insulin and IGF-1 receptors (IR and IGF1R, respectively) were resistant to apoptosis induced through either the intrinsic or the extrinsic pathway. This resistance to apoptosis was associated with decreased abundance of the proapoptotic protein Bax and increases in abundance of the antiapoptotic proteins Bcl-2, Bcl-xL, XIAP, and Flip. These cha ...[more]

PMID: 21139139

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Project description:BackgroundClinical complications associated with atherosclerotic plaques arise from luminal obstruction due to plaque growth or destabilization leading to rupture. We previously demonstrated that overexpression of insulin receptor isoform A (IRA) and insulin-like growth factor-I receptor (IGF-IR) confers a proliferative and migratory advantage to vascular smooth muscle cells (VSMCs) promoting plaque growth in early stages of atherosclerosis. However, the role of insulin receptor (IR) isoforms, IGF-IR or insulin-like growth factor-II receptor (IGF-IIR) in VSMCs apoptosis during advanced atherosclerosis remains unclear.MethodsWe evaluated IR isoforms expression in human carotid atherosclerotic plaques by consecutive immunoprecipitations of insulin receptor isoform B (IRB) and IRA. Western blot analysis was performed to measure IGF-IR, IGF-IIR, and ?-smooth muscle actin (?-SMA) expression in human plaques. The expression of those proteins, as well as the presence of apoptotic cells, was analyzed by immunohistochemistry in experimental atherosclerosis using BATIRKO; ApoE-/- mice, a model showing more aggravated vascular damage than ApoE-/- mice. Finally, apoptosis of VSMCs bearing IR (IRLoxP+/+ VSMCs), or not (IR-/- VSMCs), expressing IRA (IRA VSMCs) or expressing IRB (IRB VSMCs), was assessed by Western blot against cleaved caspase 3.ResultsWe observed a significant decrease of IRA/IRB ratio in human complicated plaques as compared to non-complicated regions. Moreover, complicated plaques showed a reduced IGF-IR expression, an increased IGF-IIR expression, and lower levels of ?-SMA indicating a loss of VSMCs. In experimental atherosclerosis, we found a significant decrease of IRA with an increased IRB expression in aorta from 24-week-old BATIRKO; ApoE-/- mice. Furthermore, atherosclerotic plaques from BATIRKO; ApoE-/- mice had less VSMCs content and higher number of apoptotic cells. In vitro experiments showed that IGF-IR inhibition by picropodophyllin induced apoptosis in VSMCs. Apoptosis induced by thapsigargin was lower in IR-/- VSMCs expressing higher IGF-IR levels as compared to IRLoxP+/+ VSMCs. Finally, IRB VSMCs are more prone to thapsigargin-induced apoptosis than IRA or IRLoxP+/+ VSMCs.ConclusionsIn advanced human atherosclerosis, a reduction of IRA/IRB ratio, decreased IGF-IR expression, or increased IGF-IIR may contribute to VSMCs apoptosis, promoting plaque instability and increasing the risk of plaque rupture and its clinical consequences.

Project description:Interventions that delay ageing mobilize mechanisms that protect and repair cellular components, but it is unknown how these interventions might slow the functional decline of extracellular matrices, which are also damaged during ageing. Reduced insulin/IGF-1 signalling (rIIS) extends lifespan across the evolutionary spectrum, and in juvenile Caenorhabditis elegans also allows the transcription factor DAF-16/FOXO to induce development into dauer, a diapause that withstands harsh conditions. It has been suggested that rIIS delays C. elegans ageing through activation of dauer-related processes during adulthood, but some rIIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits. Here we show that rIIS can promote C. elegans longevity through a program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) orthologue SKN-1 acting in parallel to DAF-16. SKN-1 is inhibited by IIS and has been broadly implicated in longevity, but is rendered dispensable for rIIS lifespan extension by even mild activity of dauer-related processes. When IIS is decreased under conditions that do not induce dauer traits, SKN-1 most prominently increases expression of collagens and other extracellular matrix genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood extracellular matrix remodelling, and are needed for ageing to be delayed by interventions that do not involve dauer traits. By genetically delineating a dauer-independent rIIS ageing pathway, our results show that IIS controls a broad set of protective mechanisms during C. elegans adulthood, and may facilitate elucidation of processes of general importance for longevity. The importance of collagen production in diverse anti-ageing interventions implies that extracellular matrix remodelling is a generally essential signature of longevity assurance, and that agents promoting extracellular matrix youthfulness may have systemic benefit.

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A kinase-independent role for unoccupied insulin and IGF-1 receptors in the control of apoptosis.

Publications

A kinase-independent role for unoccupied insulin and IGF-1 receptors in the control of apoptosis.

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