c-Myb inhibits myogenic differentiation through repression of MyoD

Kašpar, Petr; Pajer, Petr; Sedlák, David; Tamaoki, Taiki; Dvořák, Michal

doi:10.1016/j.yexcr.2005.06.016

Cited by 20 publications

(24 citation statements)

References 55 publications

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“…34 Recently, it was demonstrated that c-Myb is involved in suppression of MyoD transcriptional activity in skeletal myoblast precursors. 35 Consequently, we cannot exclude a possible role for c-Myb in promoting SMC progenitor growth.…”

Section: Discussionmentioning

confidence: 96%

c-Myb–Dependent Smooth Muscle Cell Differentiation

Kolodziejska

Noyan-Ashraf

Nagy

et al. 2008

Circulation Research

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Abstract-Both in vitro and in vivo studies have implicated the c-Myb transcription factor in vascular smooth muscle cell (SMC) proliferation and hematopoiesis. However, its role in differentiation and maturation of contractile, as opposed to proliferating, SMCs has not been investigated. Here we demonstrate that c-myb Ϫ/Ϫ embryonic stem cells (ESCs) are incapable of producing embryoid bodies (EBs) with spontaneously contracting SMCs but can differentiate into contracting cardiomyocytes unimpaired. Quantitative real-time RT-PCR revealed that whereas mesodermal differentiation was unaffected, myocardin, a critical determinant of SMC differentiation, became upregulated at day 7 in wild-type, but not in c-myb Ϫ/Ϫ EBs. SMC-specific genes, smooth muscle ␣-actin, SM22␣ and smooth muscle myosin heavy chain reached peak expression levels by day 15 of differentiation and were 2-to 3-fold higher in wild-type as compared with c-myb Ϫ/Ϫ derived EBs. Similarly, fluorescence-activated cell-sorting analysis confirmed significantly different proportions of smooth muscle ␣-actin-positive cells in wild-type (26.8Ϯ0.7%) versus c-myb Ϫ/Ϫ (12.3Ϯ0.4%) EBs. Temporal induction of these SMC-specific markers preceded and paralleled contractile SMC appearance and predicted the relative (in)ability of c-myb Ϫ/Ϫ and wild-type ESC lines to generate EBs with contracting SMCs. Importantly, data from EBs faithfully predicted a significant reduction in c-myb Ϫ/Ϫ cell contribution to SMC lineage in vivo, in chimeric E11.5 embryo and adult aortas relative to brain and skin chimerism, respectively. Moreover, the visceral SMC population in chimeric embryos was nearly devoid of c-myb Ϫ/Ϫ cells. Our data are the first to implicate c-Myb in SMC differentiation from precursor stem cell-derived populations, reinforcing its potential role in phenotypic modulation of SMCs and vascular disease.

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Section: Discussionmentioning

confidence: 96%

c-Myb–Dependent Smooth Muscle Cell Differentiation

Kolodziejska

Noyan-Ashraf

Nagy

et al. 2008

Circulation Research

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“…32,59 In proliferating myoblasts c-Myb binds MyoD, another basic HLH factor, and inhibits its transcriptional activity until cell-cell contacts are established, and c-Myb expression is switched off. 60 Because Bcl-2 is one of c-Myb targets, 61 it is conceivable that hASH1 may activate c-Myb, which will promote Bcl-2 expression in the airway epithelium of transgenic mice. So c-Myb/Bcl-2 pathway may play a crucial role in hASH1-induced proliferation and antiapoptosis in airway epithelium.…”

Section: Discussionmentioning

confidence: 99%

Achaete-scute homolog-1 linked to remodeling and preneoplasia of pulmonary epithelium

Wang

Dakir

Naizhen

et al. 2007

Laboratory Investigation

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The basic helix-loop-helix protein achaete-scute homolog-1 (ASH1) is involved in lung neuroendocrine (NE) differentiation and tumor promotion in SV40 transgenic mice. Constitutive expression of human ASH-1 (hASH1) in mouse lung results in hyperplasia and remodeling that mimics bronchiolization of alveoli (BOA), a potentially premalignant lesion of human lung carcinomas. We now show that this is due to sustained cellular proliferation in terminal bronchioles and resistance to apoptosis. Throughout the airway epithelium the expression of anti-apoptotic Bcl-2 and c-Myb was increased and Akt/mTOR pathway activated. Moreover, the expression of matrix metalloproteases (MMPs) including MMP7 was specifically enhanced at the bronchiolo-alveolar duct junction and BOA suggesting that MMPs play a key role in this microenvironment during remodeling. We also detected MMP7 in 70% of human BOA lesions. Knockdown of hASH1 gene in human lung cancer cells in vitro suppressed growth by increasing apoptosis. We also show that forced expression of hASH1 in immortalized human bronchial epithelial cells decreases apoptosis. We conclude that the impact of hASH1 is not limited to cells with NE phenotype. Rather, constitutive expression of hASH1 in lung epithelium promotes remodeling through multiple pathways that are commonly activated during lung carcinogenesis. The collective results suggest a novel model of BOA formation via hASH1-induced suppression of the apoptotic pathway. Our study yields a promising new preclinical tool for chemoprevention of peripheral lung carcinomas. KEYWORDS: achaete-scute homolog 1; apoptosis; bronchiolization of alveoli; lung; mouse model; preneoplasia; proliferation Lung cancer is the leading cause of cancer deaths in both men and women in the United States. The 5-year survival rate has remained low (15%), because the disease is generally detected at advanced and disseminated stage. 1 Contributing to the late diagnosis is the fact that precursor lesions for most lung cancer types are poorly understood. We have previously shown that the deletion of achaete-scute homolog-1 (ASH1, ASCL1), a proneural transcription factor, highly expressed in lung neuroendocrine (NE) cancers leads to the absence of pulmonary NE cells (PNECs), potential progenitors for NE cancers. 2 Constitutive expression of human ASH1 (hASH1) in the airway epithelium, on the other hand, results in epithelial proliferation and metaplasia suggesting a preneoplastic phenotype.ASH1 belongs to a diverse family of transcriptional regulators involved in fetal development and cancer that utilize the evolutionarily conserved basic helix-loop-helix (bHLH) motif. 3 Murine ASH1 (mASH1) plays a critical role in the development of the brain and the diffuse NE system including adrenal medullary chromaffin cells, thyroid parafollicular C cells, glomus chief cells and PNECs, 2,4-8 potential progenitors for small cell lung cancer (SCLC). During neurogenesis mASH1 expression is confined to mitotically active precursors where it is involved in the early stages o...

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“…Kaspar et al (2005) reported that c-Myb directly interacts with MyoD, a bHLH factor, to repress differentiation of myoblasts, and Agarwal et al (2006) found that the MYB15/ICE1(bHLH) complex binds to cis-elements upstream of CBF promoters to mediate cold responses of Arabidopsis. It should be pointed out that both LAF1 and HFR1 bind to the COP1 E3 ligase, which contains WD40 repeats (Seo et al 2003;Jang et al 2005), and with respect to this finding, a MYB/bHLH/WD40 protein complex has been shown to specify epidermal cell fate (Ramsay and Glover 2005).…”

Section: Laf1 Interacts With Hfr1mentioning

confidence: 99%

“…In this work, we investigated whether LAF1 and HFR1 control the same or different phyA signaling pathways. Because MYB/bHLH interaction has been previously reported for both plant (Grotewold et al 2000;Zimmermann et al 2004;Quattrocchio et al 2006) and animal systems (Kaspar et al 2005), we also examined possible LAF1/HFR1 interaction in phyA photoresponses. Here, we show that HFR1 and LAF1 regulate largely independent pathways downstream from phyA.…”

mentioning

confidence: 99%