Direct Interaction of c-Myc with Smad2 and Smad3 to Inhibit TGF-β-Mediated Induction of the CDK Inhibitor p15Ink4B

Feng, Xin‐Hua; Liang, Yao-Yun; Liang, Min; Zhai, Weiguo; Lin, Xia

doi:10.1016/s1097-2765(01)00430-0

Cited by 193 publications

(84 citation statements)

References 45 publications

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“…Also, p21 Cip1 induction or ID-1 reduction caused by TGF-b were not at all compromised in cells in which Smad4 downregulation restored c-Myc expression (Figures 2c, 4c). The apparent contradiction for the role of c-Myc in p15 and p21 expression can eventually be resolved by recent observations, indicating that Smads may function as 'cofactors' for c-Myc in multicomponent transcriptional complexes Feng et al, 2002). According to this model the reduced amounts of Smad3 or Smad4 in our approach interfere with inhibition of the c-myc promoter, but at the same time may be too limited to function as corepressors for c-Myc-mediated p15 suppression.…”

Section: Discussionmentioning

confidence: 73%

Differential regulation of TGF-β signaling through Smad2, Smad3 and Smad4

Kretschmer¹,

Moepert²,

Dames³

et al. 2003

Oncogene

120

100

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Smad transcription factors mediate the growth inhibitory effect of transforming growth factor-b (TGF-b) in many cell types. Mutational inactivation of Smads has been correlated with loss of responsiveness to TGF-b-mediated signal transduction. In this study, we compare the contribution of individual Smads to TGF-b-induced growth inhibition and endogenous gene expression in isogenic cellular backgrounds. Smad2, Smad3 and Smad4 expression were selectively inhibited in differentiationcompetent cells by using improved antisense molecules. We found that TGF-b mediates its inhibitory effect on HaCaT keratinocyte cell growth predominantly through Smad3. Inhibition of Smad3 expression was sufficient to interfere with TGF-b-induced cell cycle arrest and to induce or suppress endogenous cell cycle regulators. Inhibition of Smad4 expression exhibited a partial effect, whereas inhibition of Smad2 expression had no effect. By gene expression profiling, we identified TGF-b-dependent genes that are differentially regulated by Smad2 and Smad3 under regular growth conditions on a genome-wide scale. We show that Smad2, Smad3 and Smad4 contribute to the regulation of TGF-b responses to varying extents, and demonstrate, in addition, that these Smads exhibit distinct roles in different cell types.

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Section: Discussionmentioning

confidence: 73%

Differential regulation of TGF-β signaling through Smad2, Smad3 and Smad4

Kretschmer¹,

Moepert²,

Dames³

et al. 2003

Oncogene

120

100

View full text Add to dashboard Cite

show abstract

“…The proximal regions of the p21 Cip1 or p15 INKb promoters are known to mediate the transcriptional activation of the p21 Cip1 or p15 INKb promoters by members of the Smad family of proteins, which play an important role in the transduction of extracellular signals such as TGF-b, activin, etc. (Moustakas and Kardassis, 1998;Feng et al, 2002). As shown in Figure 9, Smad complex binding induced by TGF-b1 treatment was markedly decreased in SRF expressing SNU620 cells.…”

Section: Srf Inhibits Endogenous Smad Complex Formation and Smad Bindmentioning

confidence: 79%

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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“…The Smad proteins regulate transcription of the cyclindependent kinase inhibitor p21 Waf-1 (Pardali et al, 2000), which together with p15 INK4b (Feng et al, 2002), mediate the antiproliferative and tumor suppressor activity of TGF-b. Increased p21 Waf-1 protein levels appear to be essential for TGF-b-mediated inhibition of the cyclindependent kinase CDK2 (reviewed by Moustakas et al, 2002).…”

Section: Ski Represses Induction Of P21 Waf-1 By Tgf-bmentioning

confidence: 99%

Repression of TGF-β signaling by the oncogenic protein SKI in human melanomas: consequences for proliferation, survival, and metastasis

Medrano

2003

Oncogene

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Transforming growth factor-b (TGF-b) has dual and paradoxical functions as a tumor suppressor and promoter of tumor progression and metastasis. TGF-b-mediated growth inhibition is gradually lost during melanoma tumor progression, but there are no measurable defects at the receptor level. Furthermore, melanoma cells release high levels of TGF-b to the microenvironment, which upon activation induces matrix deposition, angiogenesis, survival, and transition to more aggressive phenotypes. The SKI and SnoN protein family associate with and repress the activity of Smad2, Smad3, and Smad4, three members of the TGF-b signaling pathway. SKI also facilitates cellcycle progression by targeting the RB pathway by at least two ways: it directly associates with RB and represses its activity when expressed at high levels, and indirectly, it represses Smad-mediated induction of p21 Waf-1 . This results in increased CDK2 activity, RB phosphorylation, and inactivation. Therefore, high levels of SKI result in lesions to the RB pathway in a manner similar to p16 INK4a loss. SKI mRNA and protein levels dramatically increase during human melanoma tumor progression. In addition, the SKI protein shifts from nuclear localization in intraepidermal melanoma cells to nuclear and cytoplasmic in invasive and metastatic melanomas. Here, I discuss the basis for repression of intracellular TGF-b signaling by SKI, some additional activities of this protein, and propose that by disrupting multiple tumor suppressor pathways, SKI functions as a melanoma oncogene.

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Direct Interaction of c-Myc with Smad2 and Smad3 to Inhibit TGF-β-Mediated Induction of the CDK Inhibitor p15Ink4B

Cited by 193 publications

References 45 publications

Differential regulation of TGF-β signaling through Smad2, Smad3 and Smad4

Differential regulation of TGF-β signaling through Smad2, Smad3 and Smad4

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

Repression of TGF-β signaling by the oncogenic protein SKI in human melanomas: consequences for proliferation, survival, and metastasis

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