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RhoA controls retinoid signaling by ROCK dependent regulation of retinol metabolism.

ABSTRACT: The ubiquitously expressed small GTPase RhoA is essential for embryonic development and mutated in different cancers. Functionally, it is well described as a regulator of the actin cytoskeleton, but its role in gene regulation is less understood. Using primary mouse keratinocytes with a deletion of the RhoA gene, we have now been exploring how the loss of RhoA affects gene expression. Performing transcription factor reporter assays, we found a significantly decreased activity of a RAR luciferase reporter in RhoA-null keratinocytes. Inhibition of the RhoA effector ROCK in control cells reproduced this phenotype. ATRA and retinal, but not retinol increased RAR reporter activity of keratinocytes with impaired RhoA/ROCK signaling, suggesting that retinol metabolism is regulated by RhoA/ROCK signaling. Furthermore a significant percentage of known ATRA target genes displayed altered expression in RhoA-null keratinocytes. These data reveal an unexpected link between the cytoskeletal regulator RhoA and retinoid signaling and uncover a novel pathway by which RhoA regulates gene expression.

SUBMITTER: Garcia-Mariscal A

PROVIDER: S-EPMC5997168 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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RhoA controls retinoid signaling by ROCK dependent regulation of retinol metabolism.

García-Mariscal Alberto A Peyrollier Karine K Basse Astrid A Pedersen Esben E Rühl Ralph R van Hengel Jolanda J Brakebusch Cord C

Small GTPases 20161116 5

The ubiquitously expressed small GTPase RhoA is essential for embryonic development and mutated in different cancers. Functionally, it is well described as a regulator of the actin cytoskeleton, but its role in gene regulation is less understood. Using primary mouse keratinocytes with a deletion of the RhoA gene, we have now been exploring how the loss of RhoA affects gene expression. Performing transcription factor reporter assays, we found a significantly decreased activity of a RAR luciferase ...[more]

PMID: 27754752

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Project description:AimsTo determine the mechanisms by which the ?1A-adrenergic receptor (AR) regulates cardiac contractility.BackgroundWe reported previously that transgenic mice with cardiac-restricted ?1A-AR overexpression (?1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this G?q/11-coupled receptor in hypertrophy.MethodsContractility, calcium (Ca(2+)) kinetics and sensitivity, and contractile proteins were examined in cardiomyocytes, isolated hearts and skinned fibers from ?1A-TG mice (170-fold overexpression) and their non-TG littermates (NTL) before and after ?1A-AR agonist stimulation and blockade, angiotensin II (AngII), and Rho kinase (ROCK) inhibition.ResultsHypercontractility without hypertrophy with ?1A-AR overexpression is shown to result from increased intracellular Ca(2+) release in response to agonist, augmenting the systolic amplitude of the intracellular Ca(2+) concentration [Ca(2+)]i transient without changing resting [Ca(2+)]i. In the absence of agonist, however, ?1A-AR overexpression reduced contractility despite unchanged [Ca(2+)]i. This hypocontractility is not due to heterologous desensitization: the contractile response to AngII, acting via its G?q/11-coupled receptor, was unaltered. Rather, the hypocontractility is a pleiotropic signaling effect of the ?1A-AR in the absence of agonist, inhibiting RhoA/ROCK activity, resulting in hypophosphorylation of both myosin phosphatase targeting subunit 1 (MYPT1) and cardiac myosin light chain 2 (cMLC2), reducing the Ca(2+) sensitivity of the contractile machinery: all these effects were rapidly reversed by selective ?1A-AR blockade. Critically, ROCK inhibition in normal hearts of NTLs without ?1A-AR overexpression caused hypophosphorylation of both MYPT1 and cMLC2, and rapidly reduced basal contractility.ConclusionsWe report for the first time pleiotropic ?1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart.

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RhoA controls retinoid signaling by ROCK dependent regulation of retinol metabolism.

Publications

RhoA controls retinoid signaling by ROCK dependent regulation of retinol metabolism.

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