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Muscle ring finger protein-1 inhibits PKC{epsilon} activation and prevents cardiomyocyte hypertrophy.

Arya R, Kedar V, Hwang JR, McDonough H, Li HH, Taylor J, Patterson C - J. Cell Biol. (2004)

Bottom Line: Much effort has focused on characterizing the signal transduction cascades that are associated with cardiac hypertrophy.MURF1 inhibits focal adhesion formation, and the activity of downstream effector ERK1/2 is also inhibited in the presence of MURF1.MURF1 inhibits phenylephrine-induced (but not IGF-1-induced) increases in cell size.

View Article: PubMed Central - PubMed

Affiliation: Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC 27599, USA.

ABSTRACT
Much effort has focused on characterizing the signal transduction cascades that are associated with cardiac hypertrophy. In spite of this, we still know little about the mechanisms that inhibit hypertrophic growth. We define a novel anti-hypertrophic signaling pathway regulated by muscle ring finger protein-1 (MURF1) that inhibits the agonist-stimulated PKC-mediated signaling response in neonatal rat ventricular myocytes. MURF1 interacts with receptor for activated protein kinase C (RACK1) and colocalizes with RACK1 after activation with phenylephrine or PMA. Coincident with this agonist-stimulated interaction, MURF1 blocks PKCepsilon translocation to focal adhesions, which is a critical event in the hypertrophic signaling cascade. MURF1 inhibits focal adhesion formation, and the activity of downstream effector ERK1/2 is also inhibited in the presence of MURF1. MURF1 inhibits phenylephrine-induced (but not IGF-1-induced) increases in cell size. These findings establish that MURF1 is a key regulator of the PKC-dependent hypertrophic response and can blunt cardiomyocyte hypertrophy, which may have important implications in the pathophysiology of clinical cardiac hypertrophy.

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MURF1 colocalizes with RACK1 in cultured cardiac myocytes. Rat cardiac myocytes were infected with recombinant adenovirus Ad.GFP (A and B) or Ad.MURF1 (C and D) for 24 h in serum free medium followed by induction with PE (B and D) for 48 h. Immunostaining was done with anti-Myc and anti-RACK1 antibodies. This was followed by secondary antibody incubation with anti–rabbit Alexa 568 (red) and anti–mouse AMCA (blue). The green color represents GFP expression.
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fig2: MURF1 colocalizes with RACK1 in cultured cardiac myocytes. Rat cardiac myocytes were infected with recombinant adenovirus Ad.GFP (A and B) or Ad.MURF1 (C and D) for 24 h in serum free medium followed by induction with PE (B and D) for 48 h. Immunostaining was done with anti-Myc and anti-RACK1 antibodies. This was followed by secondary antibody incubation with anti–rabbit Alexa 568 (red) and anti–mouse AMCA (blue). The green color represents GFP expression.

Mentions: Previous papers have shown that MURF1 localizes in the cytosol, sarcomeres, and nuclei of myocytes (McElhinny et al., 2002), whereas RACK1 is present in the cytosol (Ron et al., 1995, 1999). However, after activation with PMA, RACK1 is localized in perinuclear structures (Ron et al., 1995, 1999). We also observed similar staining of MURF1 and RACK1 in Ad.MURF1-infected NRVM (Fig. 2, A–C). In addition, we observed enhanced colocalization of MURF1 with RACK1 in the perinuclear region after activation with PE (Fig. 2 D). Stimulation with PMA resulted in similar colocalization of MURF1 with RACK1 from the cytosol and sarcomere to the perinuclear region and nucleus (unpublished data). These data indicate that MURF1 colocalizes with RACK1 after activation in NRVM, placing MURF1 in the right place and time to modulate RACK1-dependent signaling.


Muscle ring finger protein-1 inhibits PKC{epsilon} activation and prevents cardiomyocyte hypertrophy.

Arya R, Kedar V, Hwang JR, McDonough H, Li HH, Taylor J, Patterson C - J. Cell Biol. (2004)

MURF1 colocalizes with RACK1 in cultured cardiac myocytes. Rat cardiac myocytes were infected with recombinant adenovirus Ad.GFP (A and B) or Ad.MURF1 (C and D) for 24 h in serum free medium followed by induction with PE (B and D) for 48 h. Immunostaining was done with anti-Myc and anti-RACK1 antibodies. This was followed by secondary antibody incubation with anti–rabbit Alexa 568 (red) and anti–mouse AMCA (blue). The green color represents GFP expression.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172633&req=5

fig2: MURF1 colocalizes with RACK1 in cultured cardiac myocytes. Rat cardiac myocytes were infected with recombinant adenovirus Ad.GFP (A and B) or Ad.MURF1 (C and D) for 24 h in serum free medium followed by induction with PE (B and D) for 48 h. Immunostaining was done with anti-Myc and anti-RACK1 antibodies. This was followed by secondary antibody incubation with anti–rabbit Alexa 568 (red) and anti–mouse AMCA (blue). The green color represents GFP expression.
Mentions: Previous papers have shown that MURF1 localizes in the cytosol, sarcomeres, and nuclei of myocytes (McElhinny et al., 2002), whereas RACK1 is present in the cytosol (Ron et al., 1995, 1999). However, after activation with PMA, RACK1 is localized in perinuclear structures (Ron et al., 1995, 1999). We also observed similar staining of MURF1 and RACK1 in Ad.MURF1-infected NRVM (Fig. 2, A–C). In addition, we observed enhanced colocalization of MURF1 with RACK1 in the perinuclear region after activation with PE (Fig. 2 D). Stimulation with PMA resulted in similar colocalization of MURF1 with RACK1 from the cytosol and sarcomere to the perinuclear region and nucleus (unpublished data). These data indicate that MURF1 colocalizes with RACK1 after activation in NRVM, placing MURF1 in the right place and time to modulate RACK1-dependent signaling.

Bottom Line: Much effort has focused on characterizing the signal transduction cascades that are associated with cardiac hypertrophy.MURF1 inhibits focal adhesion formation, and the activity of downstream effector ERK1/2 is also inhibited in the presence of MURF1.MURF1 inhibits phenylephrine-induced (but not IGF-1-induced) increases in cell size.

View Article: PubMed Central - PubMed

Affiliation: Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC 27599, USA.

ABSTRACT
Much effort has focused on characterizing the signal transduction cascades that are associated with cardiac hypertrophy. In spite of this, we still know little about the mechanisms that inhibit hypertrophic growth. We define a novel anti-hypertrophic signaling pathway regulated by muscle ring finger protein-1 (MURF1) that inhibits the agonist-stimulated PKC-mediated signaling response in neonatal rat ventricular myocytes. MURF1 interacts with receptor for activated protein kinase C (RACK1) and colocalizes with RACK1 after activation with phenylephrine or PMA. Coincident with this agonist-stimulated interaction, MURF1 blocks PKCepsilon translocation to focal adhesions, which is a critical event in the hypertrophic signaling cascade. MURF1 inhibits focal adhesion formation, and the activity of downstream effector ERK1/2 is also inhibited in the presence of MURF1. MURF1 inhibits phenylephrine-induced (but not IGF-1-induced) increases in cell size. These findings establish that MURF1 is a key regulator of the PKC-dependent hypertrophic response and can blunt cardiomyocyte hypertrophy, which may have important implications in the pathophysiology of clinical cardiac hypertrophy.

Show MeSH
Related in: MedlinePlus