Inactivation of Myocardin and p16 during Malignant Transformation Contributes to a Differentiation Defect

Milyavsky, Michael; Shats, Igor; Cholostoy, Alina; Brosh, Ran; Buganim, Yosef; Weisz, Lilach; Kogan, Ira; Cohen, Michal; Shatz, Maria; Madar, Shalom; Kalo, Eyal; Goldfinger, Naomi; Yuan, Jun; Ron, Shulamit; MacKenzie, Karen L.; Eden, Amir; Rotter, Varda

doi:10.1016/j.ccr.2006.11.022

Cited by 70 publications

(83 citation statements)

References 33 publications

(39 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This observation is consistent with a recent report in which inactivation of myocardin is associated with malignant tumor growth (9). In addition, we demonstrate the endogenous influence of myocardin to hinder cell growth.…”

Section: Discussionsupporting

confidence: 82%

“…We have shown that the toggling of SRF toward growthdependent or differentiation pathways is related to interplay between myocardin and another SRF-associated factor, Elk-1, in a manner where myocardin directly competes with Elk-1 for SRF binding and antagonizes proliferative signaling induced by PDGF (7). Although previous studies have shown that overexpression of myocardin can retard cell growth (8) and inactivation of myocardin promotes tumor growth (9), the molecular mechanism related to myocardin and cellular proliferation remains unknown.…”

mentioning

confidence: 93%

See 1 more Smart Citation

Myocardin inhibits cellular proliferation by inhibiting NF-κB(p65)-dependent cell cycle progression

Tang

Zheng

Callis

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

101

106

View full text Add to dashboard Cite

We previously reported the importance of the serum response factor (SRF) cofactor myocardin in controlling muscle gene expression as well as the fundamental role for the inflammatory transcription factor NF-B in governing cellular fate. Inactivation of myocardin has been implicated in malignant tumor growth. However, the underlying mechanism of myocardin regulation of cellular growth remains unclear. Here we show that NF-B(p65) represses myocardin activation of cardiac and smooth muscle genes in a CArG-box-dependent manner. Consistent with their functional interaction, p65 directly interacts with myocardin and inhibits the formation of the myocardin/SRF/CArG ternary complex in vitro and in vivo. Conversely, myocardin decreases p65-mediated target gene activation by interfering with p65 DNA binding and abrogates LPS-induced TNF-␣ expression. Importantly, myocardin inhibits cellular proliferation by interfering with NF-B-dependent cell-cycle regulation. Cumulatively, these findings identify a function for myocardin as an SRF-independent transcriptional repressor and cell-cycle regulator and provide a molecular mechanism by which interaction between NF-B and myocardin plays a central role in modulating cellular proliferation and differentiation.cell differentiation ͉ serum response factor

show abstract

Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 93%

Myocardin inhibits cellular proliferation by inhibiting NF-κB(p65)-dependent cell cycle progression

Tang

Zheng

Callis

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

101

106

View full text Add to dashboard Cite

show abstract

“…16,25,73 TGF-b-induced responses require Smad2 and the smooth muscle transcriptional regulator myocardin. 74 The above-mentioned observations support the opinion that TGF-b is a dominant indirect proinvasive factor for epithelial cancer cells, as it converts a-SMA negative fibroblasts that do not stimulate invasion into a-SMA positive myofibroblasts that do stimulate invasion. We FIGURE 3 -Molecular cross-signaling between myofibroblasts and cancer cells.…”

Section: Characterization and Origin Of A Myofibroblastsupporting

confidence: 71%

Stromal myofibroblasts are drivers of invasive cancer growth

Wever¹,

Demetter²,

Mareel³

et al. 2008

Intl Journal of Cancer

623

601

View full text Add to dashboard Cite

Tissue integrity is maintained by the stroma in physiology. In cancer, however, tissue invasion is driven by the stroma. Myofibroblasts and cancer-associated fibroblasts are important components of the tumor stroma. The origin of myofibroblasts remains controversial, although fibroblasts and bone marrow-derived precursors are considered to be the main progenitor cells. Myofibroblast reactions also occur in fibrosis. Therefore, we wonder whether nontumorous myofibroblasts have different characteristics and different origins as compared to tumor-associated myofibroblasts. The mutual interaction between cancer cells and myofibroblasts is dependent on multiple invasive growth-promoting factors, through direct cell-cell contacts and paracrine signals. Since fibrosis is a major side effect of radiotherapy, we address the question how the main methods of cancer management, including chemotherapy, hormonotherapy and surgery affect myofibroblasts and by inference the surrogate endpoints invasion and metastasis.

show abstract

“…Consistent with this concept, a microarray screen in human skeletal myoblasts transduced with Myocd revealed repression of many genes, including Myog (19). Moreover, Myocd inhibits cell growth (20) and malignant transformation (21), although it is unclear whether these effects are due to repression of growth-regulatory genes.…”

Section: Discussionmentioning

confidence: 55%

Myocardin is a bifunctional switch for smooth versus skeletal muscle differentiation

Long

Creemers

Wang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

deacetylase ͉ myogenic ͉ SRF ͉ MEF2 ͉ promoter S keletal muscle identity is controlled primarily by four skeletal muscle-specific myogenic regulatory factors (MRFs), MyoD, myogenin (Myog), Myf5, and MRF4, which cooperate with the myocyte enhancer factor-2 (MEF2) transcription factor to activate skeletal muscle gene expression (1). Although the MRFs act in a dominant manner and can convert a variety of cell types, including smooth muscle, into skeletal muscle (2), there are settings in which skeletal muscle can be induced to transdifferentiate into other cell types, suggesting that the MRFs may be subordinate to other cell-specific transcription factors (3, 4).Much of the work related to transcriptional regulation of smooth muscle cell (SMC) differentiation has focused on serum response factor (SRF), a widely expressed transcription factor that binds the CArG box found in the regulatory regions of many SMC-specific genes (5). Genetic inactivation of SRF (6) and CArG mutagenesis studies in transgenic mice (7) have confirmed the necessity of CArG-SRF in controlling SMC differentiation. However, SRF is only a weak transcriptional activator and requires interacting cofactors that recruit proteins to promote a permissive state for gene transcription. One such cofactor is myocardin (Myocd), which is expressed primarily in cardiac and SMCs and displays high transcriptional activity (8). Myocd can activate SMC-specific genes (9), and genetic deletion of Myocd in mice leads to defective vascular SMC differentiation (10). Thus, Myocd displays features of a master regulator of the SMC phenotype.In an effort to define the cells of the cardiovascular system derived from Myocd-dependent lineages, we performed lineage tracing in mouse embryos by introducing Cre recombinase into the Myocd locus and monitoring the expression of a Credependent lacZ from the ROSA26 reporter (R26R) mouse line. Consistent with previous expression data, cardiac and vascular SMCs are derived from Myocd-dependent lineages. Surprisingly, skeletal muscle in these mice also expressed lacZ, indicating its derivation from a Myocd-dependent lineage. However, rather than functioning as an activator of skeletal muscle gene expression, Myocd represses MyoD-mediated stimulation of the Myog promoter and blocks skeletal muscle differentiation in vitro. At the same time, Myocd transactivates SMC contractile protein genes, thereby converting skeletal myoblasts to an SMC phenotype. These results suggest that Myocd acts as a bifunctional switch for muscle differentiation by concurrently opposing the gene program for skeletal muscle differentiation and specifying a SMC fate. Results Myocd Is Expressed in Progenitors of Skeletal Muscle.Myocd is expressed throughout the atrial and ventricular myocardium and in a subset of vascular and visceral SMCs (8). To trace the embryonic origins of Myocd-expressing lineages, we performed lineage tracing by creating a mouse in which the first exon of Myocd was replaced with a Cre-recombinase cassette [supporting information (SI) Fig. ...

show abstract

Inactivation of Myocardin and p16 during Malignant Transformation Contributes to a Differentiation Defect

Cited by 70 publications

References 33 publications

Myocardin inhibits cellular proliferation by inhibiting NF-κB(p65)-dependent cell cycle progression

Myocardin inhibits cellular proliferation by inhibiting NF-κB(p65)-dependent cell cycle progression

Stromal myofibroblasts are drivers of invasive cancer growth

Myocardin is a bifunctional switch for smooth versus skeletal muscle differentiation

Contact Info

Product

Resources

About