Phospho-specific Smad3 signaling

Tarasewicz, Elizabeth; Jeruss, Jacqueline S.

doi:10.4161/cc.20546

Cited by 60 publications

(27 citation statements)

References 80 publications

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“…The TGF- β signaling pathway have a dual role in cancer progression, which is a tumor suppressor for normal epithelial and early stages of cancer cells, and also, it is a tumor promoter in final stages of the metastatic diseases (Kocic, 2012, Miles, 2012, Tarasewicz, 2012). Our results provide support that ERG plays a major role in prostate cancer progression through the regulation of TGF- β signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Ets Related Gene and Smad3 Proteins Collaborate to Activate Transforming Growth Factor-Beta Mediated Signaling Pathway in ETS Related Gene-Positive Prostate Cancer Cells

Fang¹,

Xu²,

Yang³

et al. 2014

j pharmaceut sci pharmacol

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TGF-β/Smads signaling plays a significant role in the regulation of growth of normal and prostate cancer cells. Smad proteins function as important mediators of intracellular signal transduction of transforming growth factor-β (TGF-β). TGF-β signaling pathway is known to regulate cell proliferation, differentiation, apoptosis and play a major role in some human diseases and cancers. Following their phosphorylation by TGF-β receptor-I, Receptor-regulated Smads (including Smad2 and Smad3 proteins) form a heteromeric complex with co-Smad (Smad4) and then translocate into the nucleus where they bind and regulate the expression of target genes. ERG (Ets Related Gene) belongs to the ETS family of transcriptional factors. Chromosomal rearrangement of TMPRSS2 gene and ERG gene has been found in majority of prostate cancers. Over-expression of full length or truncated ERG proteins have been shown to associate with a higher rate of recurrent and unfavorable prognosis of prostate cancer. In order to understand how ERG oncoprotein regulates TGF-β/Smads signaling pathway, we have studied the effect of ERG on TGF-β/Smad3 signaling pathway. In this study, we demonstrate that ERG oncoprotein physically interacts with Smad3 protein and stabilizes phospho-Smad3 protein and thereby enhance TGF-β/Smad3 signaling pathway in prostate cells. Thus, ERG oncoprotein plays an important role in prostate tumorigenesis by using a novel mechanism to activate TGF-β/Smad3 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Ets Related Gene and Smad3 Proteins Collaborate to Activate Transforming Growth Factor-Beta Mediated Signaling Pathway in ETS Related Gene-Positive Prostate Cancer Cells

Fang¹,

Xu²,

Yang³

et al. 2014

j pharmaceut sci pharmacol

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“…TGF-β is a strong activator of EMT and involved in cancer progression and metastasis [36], [37], [38]. TGF-β is recognized as a master regulator of EMT in this phenotypic transition process [36].…”

Section: Discussionmentioning

confidence: 99%

Beta-Elemene Blocks Epithelial-Mesenchymal Transition in Human Breast Cancer Cell Line MCF-7 through Smad3-Mediated Down-Regulation of Nuclear Transcription Factors

Zhang

et al. 2013

PLoS ONE

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Epithelial-mesenchymal transition (EMT) is the first step required for breast cancer to initiate metastasis. However, the potential of drugs to block and reverse the EMT process are not well explored. In the present study, we investigated the inhibitory effect of beta-elemene (ELE), an active component of a natural plant-derived anti-neoplastic agent in an established EMT model mediated by transforming growth factor-beta1 (TGF-β1). We found that ELE (40 µg/ml ) blocked the TGF-β1-induced phenotypic transition in the human breast cancer cell line MCF-7. ELE was able to inhibit TGF-β1-mediated upregulation of mRNA and protein expression of nuclear transcription factors (SNAI1, SNAI2, TWIST and SIP1), potentially through decreasing the expression and phosphorylation of Smad3, a central protein mediating the TGF-β1 signalling pathway. These findings suggest a potential therapeutic benefit of ELE in treating basal-like breast cancer.

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“…9,10 Cyclin D/CDK4 complexes are also involved in cell cycle control through the phosphorylation and regulation of members of the transforming growth factor-β (TGFβ) superfamily. 11,12 Several members of the TGFβ superfamily have crucial roles in mammary gland physiology, with the Smads functioning as downstream mediators of this signaling pathway. 13 Intact canonical TGFβ/Smad3 signaling has previously been linked to tumor suppressive cytostatic and pro-apoptotic events in early stage breast cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Based on these opposing actions in early and later stage disease, TGFβ/Smad3 signaling can have dichotomous actions in breast oncogenesis. 12 Canonical TGFβ signaling occurs through the phosphorylation of Smad3 at the C-terminus by the TGFBRI receptor. However, CDKs 4/2, in addition to other kinases, can also noncanonically phosphorylate Smad3 at multiple sites located primarily in the linker region of the protein.…”

Section: Introductionmentioning

confidence: 99%

CDK4 inhibition and doxorubicin mediate breast cancer cell apoptosis through Smad3 and survivin

Tarasewicz¹,

Hamdan²,

Straehla³

et al. 2014

Cancer Biology & Therapy

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Cyclin D1/CDK4 activity is upregulated in up to 50% of breast cancers and CDK4-mediated phosphorylation negatively regulates the TGFβ superfamily member Smad3. We sought to determine if CDK4 inhibition and doxorubicin chemotherapy could impact Smad3-mediated cell/colony growth and apoptosis in breast cancer cells. Parental and cyclin D1-overexpressing MCF7 cells were treated with CDK4 inhibitor, doxorubicin, or combination therapy and cell proliferation, apoptosis, colony formation, and expression of apoptotic proteins were evaluated using an MTS assay, TUNEL staining, 3D Matrigel assay, and apoptosis array/immunoblotting. Study cells were also transduced with WT Smad3 or a Smad3 construct resistant to CDK4 phosphorylation (5M) and colony formation and expression of apoptotic proteins were assessed. Treatment with CDK4 inhibitor/doxorubicin combination therapy, or transduction with 5M Smad3, resulted in a similar decrease in colony formation. Treating cyclin D overexpressing breast cancer cells with combination therapy also resulted in the greatest increase in apoptosis, resulted in decreased expression of anti-apoptotic proteins survivin and XIAP, and impacted subcellular localization of pro-apoptotic Smac/DIABLO. Additionally, transduction of 5M Smad3 and doxorubicin treatment resulted in the greatest change in apoptotic protein expression. Collectively, this work showed the impact of CDK4 inhibitor-mediated, Smad3-regulated tumor suppression, which was augmented in doxorubicin-treated cyclin D-overexpressing study cells.

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Phospho-specific Smad3 signaling

Cited by 60 publications

References 80 publications

Ets Related Gene and Smad3 Proteins Collaborate to Activate Transforming Growth Factor-Beta Mediated Signaling Pathway in ETS Related Gene-Positive Prostate Cancer Cells

Ets Related Gene and Smad3 Proteins Collaborate to Activate Transforming Growth Factor-Beta Mediated Signaling Pathway in ETS Related Gene-Positive Prostate Cancer Cells

Beta-Elemene Blocks Epithelial-Mesenchymal Transition in Human Breast Cancer Cell Line MCF-7 through Smad3-Mediated Down-Regulation of Nuclear Transcription Factors

CDK4 inhibition and doxorubicin mediate breast cancer cell apoptosis through Smad3 and survivin

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