Serum response factor MADS box serine -162 phosphorylation switches proliferation and myogenic gene programs

Iyer, Dinakar; Chang, David F.; Marx, Joe; Wei, Lei; Olson, Eric N.; Parmacek, Michael S.; Balasubramanyam, Ashok; Schwartz, Robert J.

doi:10.1073/pnas.0505338103

Cited by 64 publications

(57 citation statements)

References 40 publications

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“…asy, control DNA and RNA samples from asynchronous cells prior to synchronisation. Plo1p control of M-G1 gene expression phosphorylation of SRF serine residue 162 permits the specific regulation of two groups of target genes, those required for differentiation and others involved in proliferation (Iyer et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Regulation of gene expression during M-G1-phase in fission yeast through Plo1p and forkhead transcription factors

Papadopoulou

Ohkura³

et al. 2008

Journal of Cell Science

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In fission yeast the expression of several genes during M-G1 phase is controlled by binding of the PCB binding factor (PBF) transcription factor complex to Pombe cell cycle box (PCB) promoter motifs. Three components of PBF have been identified, including two forkhead-like proteins Sep1p and Fkh2p, and a MADS-box-like protein, Mbx1p. Here, we examine how PBF is controlled and reveal a role for the Polo kinase Plo1p. plo1+ shows genetic interactions with sep1+, fkh2+ and mbx1+, and overexpression of a kinase-domain mutant of plo1 abolishes M-G1-phase transcription. Plo1p binds to and directly phosphorylates Mbx1p, the first time a Polo kinase has been shown to phosphorylate a MADS box protein in any organism. Fkh2p and Sep1p interact in vivo and in vitro, and Fkh2p, Sep1p and Plo1p contact PCB promoters in vivo. However, strikingly, both Fkh2p and Plo1p bind to PCB promoters only when PCB-controlled genes are not expressed during S- and G2-phase, whereas by contrast Sep1p contacts PCBs coincident with M-G1-phase transcription. Thus, Plo1p, Fkh2p and Sep1p control M-G1-phase gene transcription through a combination of phosphorylation and cell-cycle-specific DNA binding to PCBs.

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Section: Discussionmentioning

confidence: 99%

Regulation of gene expression during M-G1-phase in fission yeast through Plo1p and forkhead transcription factors

Papadopoulou

Ohkura³

et al. 2008

Journal of Cell Science

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“…To confirm the activation of SRF by the addition of 20% serum after 24 h serum starvation, we examined the phosphorylation of SRF at Ser-103. SRF contains a number of phosphorylation sites , and it is a target of several kinase pathways (Manak and Prywes, 1991;Janknecht et al, 1992;Liu et al, 1993;Rivera et al, 1993;Iyer et al, 2003Iyer et al, , 2006. The physiological importance of these modifications remains unsettled.…”

Section: Serum Represses Tgf-b1/smad3-dependent Transcriptionmentioning

confidence: 99%

SRF is a nuclear repressor of Smad3-mediated TGF-β signaling

et al. 2006

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Serum response factor (SRF) is a widely expressed transcription factor involved in immediate-early and tissue-specific gene expression, cell proliferation and differentiation. We defined a new role of SRF as a nuclear repressor of the tumor growth factor b1 (TGF-b1) growth-inhibitory signal during cell proliferation. We show that SRF significantly inhibits the TGF-b1/Smaddependent transcription by associating with Smad3. SRF causes resistance to the TGF-b1 cytostatic response by directly repressing the Smad transcriptional activity and Smad binding to DNA. Furthermore, we demonstrated that overexpression of SRF markedly decreases the level of Smad3 complex binding to the promoters of Smad3 target genes, p15 INK4b and p21 Cip1 . This leads to the inhibition of expression of TGF-b1-responsive genes. SRF therefore acts as a nuclear repressor of Smad3-mediated TGF-b1 signaling.

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“…SRF transcriptional activity can be modulated by phosphorylation (47) and requires at least 2 major classes of cofactors (48): (a) a ternary complex factor (TCF) family of Ets domain proteins (e.g., ELK1, Sap1, and Net), predominantly regulating expression of immediate early genes, but also repressing MKL1-dependent expression, and (b) myocardin-related transcription factors (including MKL1), which are activated by Rho-actin signaling and nuclear translocation and involved predominantly in regulating cytoskeleton-related genes (25,27,49). The mechanisms by which nuclear MKL1 activates actin-related subsets of SRF-dependent genes remains unclear, but recent studies implicate ATP-dependent chromatin remodeling by Brg1 (50).…”

Section: Figurementioning

confidence: 99%

Increased SRF transcriptional activity in human and mouse skeletal muscle is a signature of insulin resistance

Jin¹,

Goldfine²,

Boes³

et al. 2011

J. Clin. Invest.

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Insulin resistance in skeletal muscle is a key phenotype associated with type 2 diabetes (T2D) for which the molecular mediators remain unclear. We therefore conducted an expression analysis of human muscle biopsies from patients with T2D; normoglycemic but insulin-resistant subjects with a parental family history (FH + ) of T2D; and family history-negative control individuals (FH -). Actin cytoskeleton genes regulated by serum response factor (SRF) and its coactivator megakaryoblastic leukemia 1 (MKL1) had increased expression in T2D and FH + groups. Furthermore, striated muscle activator of Rho signaling (STARS), an activator of SRF, was upregulated in T2D and FH + and was inversely correlated with insulin sensitivity. Skeletal muscle from insulin-resistant mice recapitulated this gene expression pattern and showed reduced G-actin and increased nuclear localization of MKL1, each of which regulates SRF activity. Overexpression of MKL1 or reduction in G-actin decreased insulin-stimulated Akt phosphorylation, whereas reduction of STARS expression increased insulin signaling and glucose uptake. Pharmacological SRF inhibition by CCG-1423 reduced nuclear MKL1 and improved glucose uptake and tolerance in insulin-resistant mice in vivo. Thus, SRF pathway alterations are linked to insulin resistance, may contribute to T2D pathogenesis, and could represent therapeutic targets.

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Serum response factor MADS box serine -162 phosphorylation switches proliferation and myogenic gene programs

Cited by 64 publications

References 40 publications

Regulation of gene expression during M-G1-phase in fission yeast through Plo1p and forkhead transcription factors

Regulation of gene expression during M-G1-phase in fission yeast through Plo1p and forkhead transcription factors

SRF is a nuclear repressor of Smad3-mediated TGF-β signaling

Increased SRF transcriptional activity in human and mouse skeletal muscle is a signature of insulin resistance

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