Inhibition of a signaling pathway in cardiac muscle cells by active mitogen-activated protein kinase kinase.

Abstract

Signaling via the Ras pathway involves sequential activation of Ras, Raf-1, mitogenactivated protein kinase kinase (MKK), and the extracellular signal-regulated (ERK) group of mitogen-activated protein (MAP) kinases. Expression from the c-Fos, atrial natriuretic factor (ANF), and myosin light chain-2 (MLC-2) promoters during phenylephrine-induced cardiac muscle cell hypertrophy requires activation of this pathway. Furthermore, constitutively active Ras or Raf-1 can mimic the action of phenylephrine in inducing expression from these promoters. In this study, we tested whether constitutively active MKK, the molecule immediately downstream of Raf, was sufficient to induce expression. Expression of constitutively active MKK induced ERK2 kinase activity and caused expression from the c-Fos promoter, but did not significantly activate expression of reporter genes under the control of either the ANF or MLC-2 promoters. Expression of CL100, a phosphatase that inactivates ERKs, prevented expression from all of the promoters. Taken together, these data suggest that ERK activation is required for expression from the Fos, ANF, and MLC-2 promoters but MKK and ERK activation is sufficient for expression only from the Fos promoter. Constitutively active MKK synergized with phenylephrine to increase expression from a c-Fos-or an APi-driven reporter. However, active MKK inhibited phenylephrine-and Raf-1-induced expression from the ANF and MLC-2 promoters. A DNA sequence in the MLC-2 promoter that is a target for inhibition by active MKK, but not CL100, was mapped to a previously characterized DNA element (HF1) that is responsible for cardiac specificity. Thus, activation of cardiac gene expression during phenylephrine-induced hypertrophy requires ERK activation but constitutive activation by MKK can inhibit expression by targeting a DNA element that controls the cardiac specificity of gene expression.

Activation of c-Jun N-Terminal Kinases and p38-Mitogen-activated Protein Kinases in Human Heart Failure Secondary to Ischaemic Heart Disease

“…60 Although there is considerable evidence that the ERKs participate in myocyte hypertrophy, 61 it is now apparent that ERKs are not the sole mediators of this response. [62][63][64] Indeed, some investigators believe that they may even be inhibitory. 62,64,65 Because GPCR agonists are now known to activate JNKs and p38-MAPKs, the role(s) of these pathways in hypertrophy is under investigation.…”

“…[62][63][64] Indeed, some investigators believe that they may even be inhibitory. 62,64,65 Because GPCR agonists are now known to activate JNKs and p38-MAPKs, the role(s) of these pathways in hypertrophy is under investigation.…”

Sodium tanshinone IIA sulfonate depresses angiotensin II-induced cardiomyocyte hypertrophy through MEK/ERK pathway

“…Many of the signaling events stimulated by Ang II are mediated by members of the mitogen-activated protein kinase (MAPK) family, including the extracellular signal-regulated kinase (ERK), the p38 and the c-Jun NH2-terminal kinase (JNK) (Thorburn et al, 1995). Among the MAPKs, ERK has been focused on the essential regulators of a hypertrophic response although JNK and p38 were recently studied in regulating cardiac hypertrophy (Sugden, 2001;Maller, 2003;Ptashne Sodium tanshinone IIA sulfonate depresses angiotensin IIinduced cardiomyocyte hypertrophy through MEK/ERK pathway and Gann, 2003).…”

Specific role of the extracellular signal-regulated kinase pathway in angiotensin II-induced cardiac hypertrophy in vitro

“…In cultured cardiac myocytes, ERKs are activated by hypertrophic stimuli such as angiotensin II (Ang II) [10], phenylephrine [11,12], endothelin 1 [12][13][14] and PMA [13], as well as cellular stresses such as mechanical stretching [15,16] or osmotic shock [17,18]. Although the role of ERKs in phenylephrineinduced cardiac hypertrophy has been studied by several investigators with different methods, reported roles of ERKs in cardiac hypertrophy vary substantially [19][20][21][22][23]. Furthermore, recent evidence indicates that agonists for the G q -coupled receptor activate not only ERKs but also other members of the MAP kinase family, namely JNK and p38 [17,[24][25][26][27][28], and that these MAP kinases are also important in cardiac hypertrophy [25,26,[29][30][31][32] (reviewed in [5]).…”