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An inherent role of microtubule network in the action of nuclear receptor.

ABSTRACT: Estrogen receptor alpha (ERalpha) functions as both a transcription factor and a mediator of rapid estrogen signaling. Recent studies have shown a role for ERalpha-interacting membranous and cytosolic proteins in ERalpha action, but our understanding of the role of the microtubule network in the modulation of ERalpha signaling remains unclear. Here we found that endogenous ERalpha associates with microtubules through the microtubule-binding protein hematopoietic PBX-interaction protein (HPIP). Biochemical and RNA-interference studies demonstrated that HPIP influences ERalpha-dependent rapid estrogen signaling by acting as a scaffold protein and recruits Src kinase and the p85 subunit of phosphatidylinositol 3-kinase to a complex with ERalpha, which in turn stimulates AKT and MAPK. We also found that ERalpha interacts with beta-tubulin through HPIP. Destabilization of microtubules activated ERalpha signaling, whereas stabilization of microtubules repressed ERalpha transcriptional activity in a HPIP-dependent manner. These findings revealed a role for HPIP-microtubule complex in regulating 17beta-estradiol-ERalpha responses in mammalian cells and discovered an inherent role of microtubules in the action of nuclear receptor.

SUBMITTER: Manavathi B

PROVIDER: S-EPMC1635113 | biostudies-literature | 2006 Oct

REPOSITORIES: biostudies-literature

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An inherent role of microtubule network in the action of nuclear receptor.

Manavathi Bramanandam B Acconcia Filippo F Rayala Suresh K SK Kumar Rakesh R

Proceedings of the National Academy of Sciences of the United States of America 20061016 43

Estrogen receptor alpha (ERalpha) functions as both a transcription factor and a mediator of rapid estrogen signaling. Recent studies have shown a role for ERalpha-interacting membranous and cytosolic proteins in ERalpha action, but our understanding of the role of the microtubule network in the modulation of ERalpha signaling remains unclear. Here we found that endogenous ERalpha associates with microtubules through the microtubule-binding protein hematopoietic PBX-interaction protein (HPIP). B ...[more]

PMID: 17043237

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Project description:Turning on cue or stopping at a red light requires attending to such cues to select action sequences, or suppress action, in accordance with learned cue-associated action rules. Cortico-striatal projections are an essential part of the brain's attention-motor interface. Glutamate-sensing microelectrode arrays were used to measure glutamate transients in the dorsomedial striatum (DMS) of male and female rats walking a treadmill and executing cued turns and stops. Prelimbic-DMS projections were chemogenetically inhibited to determine their behavioral necessity and the cortico-striatal origin of cue-evoked glutamate transients. Furthermore, we investigated rats exhibiting preferably goal-directed (goal trackers, GTs) versus cue-driven attention (sign-trackers, STs), to determine the impact of such cognitive-motivational biases on cortico-striatal control. GTs executed more cued turns and initiated such turns more slowly than STs. During turns, but not missed turns or cued stops, cue-evoked glutamate concentrations were higher in GTs than in STs. In STs, turn cue-locked glutamate concentrations frequently peaked twice or three times, contrasting with predominately single peaks in GTs. In GTs, but not STs, inhibition of prelimbic-DMS projections attenuated turn rates and turn cue-evoked glutamate concentrations and increased the number of turn cue-locked glutamate peaks. These findings indicate that turn cue-evoked glutamate release in GTs is tightly controlled by cortico-striatal neuronal activity. In contrast, in STs, glutamate release from DMS glutamatergic terminals may be regulated by other striatal circuitry, preferably mediating cued suppression of action and reward tracking. As cortico-striatal dysfunction has been hypothesized to contribute to a wide range of disorders, including complex movement control deficits in Parkinson's disease and compulsive drug taking, the demonstration of phenotypic contrasts in cortico-striatal control implies the presence of individual vulnerabilities for such disorders.

Project description:BackgroundNor1/NR4A3 is a member of the NR4A subfamily of nuclear receptors that play essential roles in regulating gene expression related to development, cell homeostasis and neurological functions. However, Nor1 is still considered an orphan receptor, as its natural ligand remains unclear for mediating transcriptional activation. Yet other activation signals may modulate Nor1 activity, although their precise role in the development and maintenance of the nervous system remains elusive.MethodsWe used transcriptional reporter assays, gene expression profiling, protein turnover measurement, and cell growth assays to assess the functional relevance of Nor1 and SUMO-defective variants in neuronal cells. SUMO1 and SUMO2 conjugation to Nor1 were assessed by immunoprecipitation. Tubulin stability was determined by acetylation and polymerization assays, and live-cell fluorescent microscopy.ResultsHere, we demonstrate that Nor1 undergoes SUMO1 conjugation at Lys-89 within a canonical ψKxE SUMOylation motif, contributing to the complex pattern of Nor1 SUMOylation, which also includes Lys-137. Disruption of Lys-89, thereby preventing SUMO1 conjugation, led to reduced Nor1 transcriptional competence and protein stability, as well as the downregulation of genes involved in cell growth and metabolism, such as ENO3, EN1, and CFLAR, and in microtubule cytoskeleton dynamics, including MAP2 and MAPT, which resulted in reduced survival of neuronal cells. Interestingly, Lys-89 SUMOylation was potentiated in response to nocodazole, a microtubule depolymerizing drug, although this was insufficient to rescue cells from microtubule disruption despite enhanced Nor1 gene expression. Instead, Lys-89 deSUMOylation reduced the expression of microtubule-severing genes like KATNA1, SPAST, and FIGN, and enhanced α-tubulin cellular levels, acetylation, and microfilament organization, promoting microtubule stability and resistance to nocodazole. These effects contrasted with Lys-137 SUMOylation, suggesting distinct regulatory mechanisms based on specific Nor1 input SUMOylation signals.ConclusionsOur study provides novel insights into Nor1 transcriptional signaling competence and identifies a hierarchical mechanism whereby selective Nor1 SUMOylation may govern neuronal cytoskeleton network dynamics and resistance against microtubule disturbances, a condition strongly associated with neurodegenerative diseases.

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An inherent role of microtubule network in the action of nuclear receptor.

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An inherent role of microtubule network in the action of nuclear receptor.

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