The human NUPR1/P8 gene is transcriptionally activated by transforming growth factor β via the SMAD signalling pathway

NUPR1 (nuclear protein 1), also called P8 (molecular mass 8 kDa) or COM1 (candidate of metastasis 1), is involved in the stress response and in cancer progression. In the present study, we investigated whether human NUPR1 expression was regulated by TGFβ (transforming growth factor β), a secreted polypeptide largely involved in tumorigenesis. We demonstrate that the expression of NUPR1 was activated by TGFβ at the transcriptional level. We show that this activation is mediated by the SMAD proteins, which are transcription factors specifically involved in the signalling of TGFβ superfamily members. NUPR1 promoter analysis reveals the presence of a functional TGFβ-response element binding the SMAD proteins located in the genomic DNA region corresponding to the 5′-UTR (5′-untranslated region). Altogether, the molecular results of the present study, which demonstrate the existence of a TGFβ/SMAD/NUPR1 activation cascade, open the way to consider and investigate further a new mechanism enabling TGFβ to promote tumorigenesis by inducing stress resistance.

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Transforming Growth Factor β-Mediated Transcriptional Repression of c-myc Is Dependent on Direct Binding of Smad3 to a Novel Repressive Smad Binding Element

Molecular and Cellular Biology ◽

10.1128/mcb.24.6.2546-2559.2004 ◽

2004 ◽

Vol 24 (6) ◽

pp. 2546-2559 ◽

Cited By ~ 159

Author(s):

Joshua P. Frederick ◽

Nicole T. Liberati ◽

David S. Waddell ◽

Yigong Shi ◽

Xiao-Fan Wang

Keyword(s):

Growth Factor ◽

Transcriptional Repression ◽

Molecular Mechanisms ◽

Target Genes ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Cell Types ◽

Specific Cell ◽

Smad Proteins ◽

Smad Binding Element

ABSTRACT Smad proteins are the most well-characterized intracellular effectors of the transforming growth factor β (TGF-β) signal. The ability of the Smads to act as transcriptional activators via TGF-β-induced recruitment to Smad binding elements (SBE) within the promoters of TGF-β target genes has been firmly established. However, the elucidation of the molecular mechanisms involved in TGF-β-mediated transcriptional repression are only recently being uncovered. The proto-oncogene c-myc is repressed by TGF-β, and this repression is required for the manifestation of the TGF-β cytostatic program in specific cell types. We have shown that Smad3 is required for both TGF-β-induced repression of c-myc and subsequent growth arrest in keratinocytes. The transcriptional repression of c-myc is dependent on direct Smad3 binding to a novel Smad binding site, termed a repressive Smad binding element (RSBE), within the TGF-β inhibitory element (TIE) of the c-myc promoter. The c-myc TIE is a composite element, comprised of an overlapping RSBE and a consensus E2F site, that is capable of binding at least Smad3, Smad4, E2F-4, and p107. The RSBE is distinct from the previously defined SBE and may partially dictate, in conjunction with the promoter context of the overlapping E2F site, whether the Smad3-containing complex actively represses, as opposed to transactivates, the c-myc promoter.

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Alteration in transforming growth factor-β receptor expression in gallbladder disease: implications of chronic cholelithiasis and chronic Salmonella typhi infection

Gastroenterology Insights ◽

10.4081/gi.2016.6623 ◽

2016 ◽

Vol 7 (1) ◽

Cited By ~ 2

Author(s):

Yogesh D. Walawalkar ◽

Yatindra Vaidya ◽

Vijayashree Nayak

Keyword(s):

Growth Factor ◽

Cancer Progression ◽

Transforming Growth Factor ◽

Receptor Gene ◽

Gallbladder Disease ◽

Fold Increase ◽

Transforming Growth Factor Β ◽

Salmonella Typhi ◽

Receptor Expression ◽

Β Receptor

Gallbladder cancer prevalence is ever increasing with Salmonella typhi chronic infection being one of the predisposing factors. Altered ratios or expression of transforming growth factor-β (TGF-β) receptors and changes in its function are associated with loss in anti-proliferative effects of TGF-β and cancer progression. Using reverse transcriptase polymerase chain reaction we monitor any changes in TGF-β receptor gene expression. We simultaneously screen for S. typhi within the samples. From 73 patients undergoing cholecystectomy 39-50% had significant expression (P<0.05) of TGF-β receptor (TβR)- I and TβR-II during chronic cholelithiasis as compared to the remaining 19-23% with acute chronic cholelithiasis. There was no significant increase in TβR-III receptor expression. Patient’s positive for S. typhi (7/73) did not show any significant changes in expression of these receptors, thus indicating no direct relation in regulating the host TGFβ-signaling pathway. Further analysis on expression of downstream Smad components revealed that patients with up-regulated TGFβ receptor expression show >2-fold increase in the RSmads and Co-Smads with a >2-fold decrease in I-Smads. Thus gain of TβR-I and II expression in epithelial cells of the gallbladder was associated with chronic inflammatory stages of the gallbladder disease.

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Transforming Growth Factor-β Signaling in Fibrotic Diseases and Cancer-Associated Fibroblasts

Biomolecules ◽

10.3390/biom10121666 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1666

Author(s):

Xueke Shi ◽

Christian D. Young ◽

Hongmei Zhou ◽

Xiao-Jing Wang

Keyword(s):

Growth Factor ◽

Cancer Progression ◽

Immune Cells ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Cell Types ◽

Cancer Associated Fibroblasts ◽

The Matrix ◽

Fibrotic Diseases ◽

Fibrotic Disorders

Transforming growth factor-β (TGF-β) signaling is essential in embryo development and maintaining normal homeostasis. Extensive evidence shows that TGF-β activation acts on several cell types, including epithelial cells, fibroblasts, and immune cells, to form a pro-fibrotic environment, ultimately leading to fibrotic diseases. TGF-β is stored in the matrix in a latent form; once activated, it promotes a fibroblast to myofibroblast transition and regulates extracellular matrix (ECM) formation and remodeling in fibrosis. TGF-β signaling can also promote cancer progression through its effects on the tumor microenvironment. In cancer, TGF-β contributes to the generation of cancer-associated fibroblasts (CAFs) that have different molecular and cellular properties from activated or fibrotic fibroblasts. CAFs promote tumor progression and chronic tumor fibrosis via TGF-β signaling. Fibrosis and CAF-mediated cancer progression share several common traits and are closely related. In this review, we consider how TGF-β promotes fibrosis and CAF-mediated cancer progression. We also discuss recent evidence suggesting TGF-β inhibition as a defense against fibrotic disorders or CAF-mediated cancer progression to highlight the potential implications of TGF-β-targeted therapies for fibrosis and cancer.

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The role of transforming growth factor-β (TGF-β) in epithelial ovarian cancer progression via immunosuppression

Gynecologic Oncology ◽

10.1016/j.ygyno.2019.04.134 ◽

2019 ◽

Vol 154 ◽

pp. 56

Author(s):

B.M. Roane ◽

S. Meza-Perez ◽

I. Betella ◽

W. Goldsberry ◽

R.C. Arend

Keyword(s):

Ovarian Cancer ◽

Growth Factor ◽

Epithelial Ovarian Cancer ◽

Cancer Progression ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β

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CREB binding protein is a required coactivator for Smad-dependent, transforming growth factor β transcriptional responses in endothelial cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.95.16.9506 ◽

1998 ◽

Vol 95 (16) ◽

pp. 9506-9511 ◽

Cited By ~ 127

Author(s):

James N. Topper ◽

Maria R. DiChiara ◽

Jonathan D. Brown ◽

Amy J. Williams ◽

Dean Falb ◽

...

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Transforming Growth Factor ◽

Binding Protein ◽

Transforming Growth Factor Β ◽

Cell Types ◽

Creb Binding Protein ◽

Transcriptional Responses ◽

Smad Proteins ◽

Smad Protein

The transforming growth factor-β (TGF-β) superfamily of growth factors and cytokines has been implicated in a variety of physiological and developmental processes within the cardiovascular system. Smad proteins are a recently described family of intracellular signaling proteins that transduce signals in response to TGF-β superfamily ligands. We demonstrate by both a mammalian two-hybrid and a biochemical approach that human Smad2 and Smad4, two essential Smad proteins involved in mediating TGF-β transcriptional responses in endothelial and other cell types, can functionally interact with the transcriptional coactivator CREB binding protein (CBP). This interaction is specific in that it requires ligand (TGF-β) activation and is mediated by the transcriptional activation domains of the Smad proteins. A closely related, but distinct endothelial-expressed Smad protein, Smad7, which does not activate transcription in endothelial cells, does not interact with CBP. Furthermore, Smad2,4–CBP interactions involve the COOH terminus of CBP, a region that interacts with other regulated transcription factors such as certain signal transduction and transcription proteins and nuclear receptors. Smad–CBP interactions are required for Smad-dependent TGF-β-induced transcriptional responses in endothelial cells, as evidenced by inhibition with overexpressed 12S E1A protein and reversal of this inhibition with exogenous CBP. This report demonstrates a functional interaction between Smad proteins and an essential component of the mammalian transcriptional apparatus (CBP) and extends our insight into how Smad proteins may regulate transcriptional responses in many cell types. Thus, functional Smad–coactivator interactions may be an important locus of signal integration in endothelial cells.

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