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Myocardin Family Members Drive Formation of Caveolae.

Krawczyk KK, Yao Mattisson I, Ekman M, Oskolkov N, Grantinge R, Kotowska D, Olde B, Hansson O, Albinsson S, Miano JM, Rippe C, Swärd K - PLoS ONE (2015)

Bottom Line: The effect of LatB was associated with reduced mRNA levels for these genes and this was replicated by the MRTF inhibitor CCG-1423 which was non-additive with LatB.Knock down of the serum response factor (SRF), which mediates many of the effects of myocardin, decreased cavin-1 but increased caveolin-1 and -2 mRNAs.The myocardin family of transcriptional coactivators therefore drives formation of caveolae and this effect is largely independent of SRF.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medical Science, BMC D12, Lund University, Lund, Sweden.

ABSTRACT
Caveolae are membrane organelles that play roles in glucose and lipid metabolism and in vascular function. Formation of caveolae requires caveolins and cavins. The make-up of caveolae and their density is considered to reflect cell-specific transcriptional control mechanisms for caveolins and cavins, but knowledge regarding regulation of caveolae genes is incomplete. Myocardin (MYOCD) and its relative MRTF-A (MKL1) are transcriptional coactivators that control genes which promote smooth muscle differentiation. MRTF-A communicates changes in actin polymerization to nuclear gene transcription. Here we tested if myocardin family proteins control biogenesis of caveolae via activation of caveolin and cavin transcription. Using human coronary artery smooth muscle cells we found that jasplakinolide and latrunculin B (LatB), substances that promote and inhibit actin polymerization, increased and decreased protein levels of caveolins and cavins, respectively. The effect of LatB was associated with reduced mRNA levels for these genes and this was replicated by the MRTF inhibitor CCG-1423 which was non-additive with LatB. Overexpression of myocardin and MRTF-A caused 5-10-fold induction of caveolins whereas cavin-1 and cavin-2 were induced 2-3-fold. PACSIN2 also increased, establishing positive regulation of caveolae genes from three families. Full regulation of CAV1 was retained in its proximal promoter. Knock down of the serum response factor (SRF), which mediates many of the effects of myocardin, decreased cavin-1 but increased caveolin-1 and -2 mRNAs. Viral transduction of myocardin increased the density of caveolae 5-fold in vitro. A decrease of CAV1 was observed concomitant with a decrease of the smooth muscle marker calponin in aortic aneurysms from mice (C57Bl/6) infused with angiotensin II. Human expression data disclosed correlations of MYOCD with CAV1 in a majority of human tissues and in the heart, correlation with MKL2 (MRTF-B) was observed. The myocardin family of transcriptional coactivators therefore drives formation of caveolae and this effect is largely independent of SRF.

No MeSH data available.


Related in: MedlinePlus

Expression of myocardin family genes correlate with expression of caveolae genes in humans.mRNA expression data was retrieved from the GTExPortal. TMM-normalized data was used to correlate expression of myocardin family genes with CAV1, CAV2 and PTRF in the tibial artery (panels A, E, I, n = 137), in esophagus (B, F, J, n = 227), in colon (C, G, K, n = 74) and in heart (D, H, L, n = 134). P-values and Spearmann Rho coefficients (R) are given in the respective panels. In all datasets where more than one tissue were represented, such as the esophagus (muscularis: red symbols; mucosa: blue symbols), we always observed significant correlations both within (red and blue P-values) and across (black P-values) tissues.
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pone.0133931.g008: Expression of myocardin family genes correlate with expression of caveolae genes in humans.mRNA expression data was retrieved from the GTExPortal. TMM-normalized data was used to correlate expression of myocardin family genes with CAV1, CAV2 and PTRF in the tibial artery (panels A, E, I, n = 137), in esophagus (B, F, J, n = 227), in colon (C, G, K, n = 74) and in heart (D, H, L, n = 134). P-values and Spearmann Rho coefficients (R) are given in the respective panels. In all datasets where more than one tissue were represented, such as the esophagus (muscularis: red symbols; mucosa: blue symbols), we always observed significant correlations both within (red and blue P-values) and across (black P-values) tissues.

Mentions: Myocardin-related coactivators may contribute to CAV1 variation in human tissues. To test this, mRNA expression data for caveolins, cavins and myocardin-related transcription factors was retrieved from the GTEx Portal. Myocardin (MYOCD) correlated significantly with CAV1 in a majority of human tissues as exemplified by tibial artery (Fig 8A) and esophagus (Fig 8B). In esophagus, correlations were seen both in the mucosa (blue in Fig 8B, 8F and 8J), in the muscularis (red), and in both tissues combined (black), arguing that MYOCD explains variation not only within but also between tissues. MKL1 (MRTF-A) also correlated with CAV1 in many tissues such as in colon (Fig 8C). Instances of negative correlations between MKL1 and CAV1 were occasionally observed. This is perhaps to be expected from competition between myocardin and MRTF-A. In heart (Fig 8D) and adipose tissue (not shown) only MKL2 correlated with CAV1. Similar correlations were seen for MYOCD vs. CAV2 and MYOCD vs. PTRF (Fig 8, panels E-L), but rare exceptions were seen (Fig 8L). A summary of the correlations observed in these tissues is provided in Table 1. Together, these observations argue that myocardin family coactivators represent a quantitatively important transcriptional control mechanism for caveolae genes in human tissues. Supporting the notion that these genes are coregulated, we also found correlations between CAV1 and CAV2, between CAV1 and PTRF and between CAV1 and SDPR in these tissues (S2 Fig, panel A). CAV1 always correlated better with CAV2 than with SDPR (c.f. S2 Fig, tibial artery or heart).


Myocardin Family Members Drive Formation of Caveolae.

Krawczyk KK, Yao Mattisson I, Ekman M, Oskolkov N, Grantinge R, Kotowska D, Olde B, Hansson O, Albinsson S, Miano JM, Rippe C, Swärd K - PLoS ONE (2015)

Expression of myocardin family genes correlate with expression of caveolae genes in humans.mRNA expression data was retrieved from the GTExPortal. TMM-normalized data was used to correlate expression of myocardin family genes with CAV1, CAV2 and PTRF in the tibial artery (panels A, E, I, n = 137), in esophagus (B, F, J, n = 227), in colon (C, G, K, n = 74) and in heart (D, H, L, n = 134). P-values and Spearmann Rho coefficients (R) are given in the respective panels. In all datasets where more than one tissue were represented, such as the esophagus (muscularis: red symbols; mucosa: blue symbols), we always observed significant correlations both within (red and blue P-values) and across (black P-values) tissues.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4526231&req=5

pone.0133931.g008: Expression of myocardin family genes correlate with expression of caveolae genes in humans.mRNA expression data was retrieved from the GTExPortal. TMM-normalized data was used to correlate expression of myocardin family genes with CAV1, CAV2 and PTRF in the tibial artery (panels A, E, I, n = 137), in esophagus (B, F, J, n = 227), in colon (C, G, K, n = 74) and in heart (D, H, L, n = 134). P-values and Spearmann Rho coefficients (R) are given in the respective panels. In all datasets where more than one tissue were represented, such as the esophagus (muscularis: red symbols; mucosa: blue symbols), we always observed significant correlations both within (red and blue P-values) and across (black P-values) tissues.
Mentions: Myocardin-related coactivators may contribute to CAV1 variation in human tissues. To test this, mRNA expression data for caveolins, cavins and myocardin-related transcription factors was retrieved from the GTEx Portal. Myocardin (MYOCD) correlated significantly with CAV1 in a majority of human tissues as exemplified by tibial artery (Fig 8A) and esophagus (Fig 8B). In esophagus, correlations were seen both in the mucosa (blue in Fig 8B, 8F and 8J), in the muscularis (red), and in both tissues combined (black), arguing that MYOCD explains variation not only within but also between tissues. MKL1 (MRTF-A) also correlated with CAV1 in many tissues such as in colon (Fig 8C). Instances of negative correlations between MKL1 and CAV1 were occasionally observed. This is perhaps to be expected from competition between myocardin and MRTF-A. In heart (Fig 8D) and adipose tissue (not shown) only MKL2 correlated with CAV1. Similar correlations were seen for MYOCD vs. CAV2 and MYOCD vs. PTRF (Fig 8, panels E-L), but rare exceptions were seen (Fig 8L). A summary of the correlations observed in these tissues is provided in Table 1. Together, these observations argue that myocardin family coactivators represent a quantitatively important transcriptional control mechanism for caveolae genes in human tissues. Supporting the notion that these genes are coregulated, we also found correlations between CAV1 and CAV2, between CAV1 and PTRF and between CAV1 and SDPR in these tissues (S2 Fig, panel A). CAV1 always correlated better with CAV2 than with SDPR (c.f. S2 Fig, tibial artery or heart).

Bottom Line: The effect of LatB was associated with reduced mRNA levels for these genes and this was replicated by the MRTF inhibitor CCG-1423 which was non-additive with LatB.Knock down of the serum response factor (SRF), which mediates many of the effects of myocardin, decreased cavin-1 but increased caveolin-1 and -2 mRNAs.The myocardin family of transcriptional coactivators therefore drives formation of caveolae and this effect is largely independent of SRF.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medical Science, BMC D12, Lund University, Lund, Sweden.

ABSTRACT
Caveolae are membrane organelles that play roles in glucose and lipid metabolism and in vascular function. Formation of caveolae requires caveolins and cavins. The make-up of caveolae and their density is considered to reflect cell-specific transcriptional control mechanisms for caveolins and cavins, but knowledge regarding regulation of caveolae genes is incomplete. Myocardin (MYOCD) and its relative MRTF-A (MKL1) are transcriptional coactivators that control genes which promote smooth muscle differentiation. MRTF-A communicates changes in actin polymerization to nuclear gene transcription. Here we tested if myocardin family proteins control biogenesis of caveolae via activation of caveolin and cavin transcription. Using human coronary artery smooth muscle cells we found that jasplakinolide and latrunculin B (LatB), substances that promote and inhibit actin polymerization, increased and decreased protein levels of caveolins and cavins, respectively. The effect of LatB was associated with reduced mRNA levels for these genes and this was replicated by the MRTF inhibitor CCG-1423 which was non-additive with LatB. Overexpression of myocardin and MRTF-A caused 5-10-fold induction of caveolins whereas cavin-1 and cavin-2 were induced 2-3-fold. PACSIN2 also increased, establishing positive regulation of caveolae genes from three families. Full regulation of CAV1 was retained in its proximal promoter. Knock down of the serum response factor (SRF), which mediates many of the effects of myocardin, decreased cavin-1 but increased caveolin-1 and -2 mRNAs. Viral transduction of myocardin increased the density of caveolae 5-fold in vitro. A decrease of CAV1 was observed concomitant with a decrease of the smooth muscle marker calponin in aortic aneurysms from mice (C57Bl/6) infused with angiotensin II. Human expression data disclosed correlations of MYOCD with CAV1 in a majority of human tissues and in the heart, correlation with MKL2 (MRTF-B) was observed. The myocardin family of transcriptional coactivators therefore drives formation of caveolae and this effect is largely independent of SRF.

No MeSH data available.


Related in: MedlinePlus