Online citations, reference lists, and bibliographies.
← Back to Search

TGF‐β Inhibits Prolactin‐induced Expression Of β‐casein By A Smad3‐dependent Mechanism

Wen-jun Wu, Chin-Feng Lee, Chung-Han Hsin, J. Du, Tsai-Ching Hsu, T. Lin, T. Yao, Cheng-Hsieh Huang, Y. Lee
Published 2008 · Biology, Medicine

Save to my Library
Download PDF
Analyze on Scholarcy
Transforming growth factor‐β (TGF‐β) is a multifunctional growth factor, affecting cell proliferation, apoptosis, and extracellular matrix homeostasis. It also plays critical roles in mammary gland development, one of which involves inhibition of the expression of milk proteins, such as β‐casein, during pregnancy. Here we further explore the underlying signaling mechanism for it. Our results show that TGF‐β suppresses prolactin‐induced expression of β‐casein mRNA and protein in primary mouse mammary epithelial cells, but its effect on protein expression is more evident. We also find out that this inhibition is not due to the effect of TGF‐β on cell apoptosis. Furthermore, inhibition of TGF‐β type I receptor kinase activity by a pharmacological inhibitor SB431542 or overexpression of dominant negative Smad3 substantially restores β‐casein expression. By contrast, inhibition of p38 and Erk that are known to be activated by TGF‐β does not alleviate the inhibitory effect of TGF‐β. These results are consistent with our other observation that Smad but not MAPK pathway is activated by TGF‐β in mammary epithelial cells. Lastly, we show that prolactin‐induced tyrosine phosphorylation of Jak2 and Stat5 as well as serine/threonine phosphorylation of p70S6K and S6 ribosomal protein are downregulated by TGF‐β, although the former event requires considerably long exposure to TGF‐β. We speculate that these events might be involved in repressing transcription and translation of β‐casein gene, respectively. Taken together, our results demonstrate that TGF‐β abrogates prolactin‐stimulated β‐casein gene expression in mammary epithelial cells through, at least in part, a Smad3‐dependent mechanism. J. Cell. Biochem. 104: 1647–1659, 2008. © 2008 Wiley‐Liss, Inc.
This paper references
Signaling pathways in mammary gland development.
L. Hennighausen (2001)
Mechanisms of TGF-beta signaling from cell membrane to the nucleus.
Y. Shi (2003)
Expression of TGF‐β type II receptor antisense RNA impairs TGF‐β signaling in vitro and promotes mammary gland differentiation in vivo
A. E. Lenferink (2003)
Effect of conditional knockout of the type II TGF-beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis.
E. Forrester (2005)
mTOR and S6K1 Mediate Assembly of the Translation Preinitiation Complex through Dynamic Protein Interchange and Ordered Phosphorylation Events
M. Holz (2005)
Transforming growth factor β signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis
P. Siegel (2003)
Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family.
H. B. Jefferies (1994)
Hormone-dependent beta-casein mRNA stabilization requires ongoing protein synthesis.
P. Poyet (1989)
Non-Smad TGF-β signals
A. Moustakas (2005)
Transforming growth factor-beta inhibits CCAAT/enhancer-binding protein expression and PPARgamma activity in unloaded bone marrow stromal cells.
S. Ahdjoudj (2005)
RAS/ERK Signaling Promotes Site-specific Ribosomal Protein S6 Phosphorylation via RSK and Stimulates Cap-dependent Translation*
Philippe P Roux (2007)
TGF-β1 Inhibits T-bet Induction by IFN-γ in Murine CD4+ T Cells through the Protein Tyrosine Phosphatase Src Homology Region 2 Domain-Containing Phosphatase-11
I. K. Park (2005)
TGF beta suppresses casein synthesis in mouse mammary explants and may play a role in controlling milk levels during pregnancy
S. Robinson (1993)
PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3.
I. Remy (2004)
The logic of TGFβ signaling
J. Massagué (2006)
Conversion of SB 203580-insensitive MAP kinase family members to drug-sensitive forms by a single amino-acid substitution.
P. Eyers (1998)
Dominant-negative interference of the transforming growth factor beta type II receptor in mammary gland epithelium results in alveolar hyperplasia and differentiation in virgin mice.
A. Gorska (1998)
Transforming growth factor-β inhibits CCAAT/enhancer-binding protein expression and PPARγ activity in unloaded bone marrow stromal cells
S. Ahdjoudj (2005)
TGF-β inhibits p70 S6 kinase via protein phosphatase 2A to induce G1 arrest
C. Petritsch (2000)
The Possible Role of TGF-β-Induced Suppressors of Cytokine Signaling Expression in Osteoclast/Macrophage Lineage Commitment In Vitro1
S. Fox (2003)
Smad-dependent and Smad-independent pathways in TGF-beta family signalling.
R. Derynck (2003)
TGF-beta1 inhibits T-bet induction by IFN-gamma in murine CD4+ T cells through the protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1.
Il-kyoo Park (2005)
The logic of TGFbeta signaling.
J. Massagué (2006)
Antagonistic Regulation of Tight Junction Dynamics by Glucocorticoids and Transforming Growth Factor- in Mouse Mammary Epithelial Cells (*)
P. Woo (1996)
Hormone-dependent β-casein mRNA stabilization requires ongoing protein synthesis
P. Poyet (1989)
Physical and functional interactions between type I transforming growth factor beta receptors and Balpha, a WD-40 repeat subunit of phosphatase 2A.
I. Griswold-Prenner (1998)
Effect of rapamycin on prolactin-stimulated S6 kinase activity and milk product formation in mouse mammary explants.
J. Hang (1997)
Mouse models of transforming growth factor beta impact in breast development and cancer.
R. Serra (2005)
p38 mitogen-activated protein kinase is required for TGFbeta-mediated fibroblastic transdifferentiation and cell migration.
Andrei V Bakin (2002)
Redirection of B cell responsiveness by transforming growth factor β receptor
J. Roes (2003)
Non-Smad TGF-beta signals.
A. Moustakas (2005)
Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis.
Igor Ruvinsky (2005)
Loss of Smad3-Mediated Negative Regulation of Runx2 Activity Leads to an Alteration in Cell Fate Determination
A. Hjelmeland (2005)
TGF-beta inhibits p70 S6 kinase via protein phosphatase 2A to induce G(1) arrest.
C. Petritsch (2000)
TGF‐β‐induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation
T. Alliston (2001)
Regulated expression and growth inhibitory effects of transforming growth factor-beta isoforms in mouse mammary gland development.
S. Robinson (1991)
TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses.
L. Yu (2002)
TGF-beta inhibits IL-2-induced tyrosine phosphorylation and activation of Jak-1 and Stat 5 in T lymphocytes.
J. Bright (1997)
p38 mitogen-activated protein kinase is required for TGFβ-mediated fibroblastic transdifferentiation and cell migration
Andrei V Bakin (2002)
TGF‐β receptor‐activated p38 MAP kinase mediates Smad‐independent TGF‐β responses
L. Yu (2002)
TGF-beta-induced SOCS3 expression augments TNF-alpha-induced osteoclast formation.
Alison C. Lovibond (2003)
Ectopic TGF beta 1 expression in the secretory mammary epithelium induces early senescence of the epithelial stem cell population.
E. Kordon (1995)
Transforming Growth Factor-β Inhibits Adipocyte Differentiation by Smad3 Interacting with CCAAT/Enhancer-binding Protein (C/EBP) and Repressing C/EBP Transactivation Function*
L. Choy (2003)
Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus
Y. Shi (2003)
Repression of Runx2 function by TGF‐β through recruitment of class II histone deacetylases by Smad3
Jong Seok Kang (2005)
Physical and Functional Interactions between Type I Transforming Growth Factor β Receptors and Bα, a WD-40 Repeat Subunit of Phosphatase 2A
I. Griswold-Prenner (1998)
Adenoviral-mediated gene transfer in two-dimensional and three-dimensional cultures of mammary epithelial cells.
Harriet Watkin (2002)
A single missense mutant of Smad3 inhibits activation of both Smad2 and Smad3, and has a dominant negative effect on TGF‐β signals
D. Goto (1998)
Smad-dependent and Smad-independent pathways in TGF-β family signalling
R. Derynck (2003)
TGF-β-induced SOCS3 expression augments TNF-α-induced osteoclast formation
Alison C. Lovibond (2003)
Prolactin and transforming growth factor-beta signaling exert opposing effects on mammary gland morphogenesis, involution, and the Akt-forkhead pathway.
J. P. Bailey (2004)
Targeting expression of a transforming growth factor beta 1 transgene to the pregnant mammary gland inhibits alveolar development and lactation.
C. Jhappan (1993)
Akt interacts directly with Smad3 to regulate the sensitivity to TGF-β-induced apoptosis
Andrew R. Conery (2004)
Glucocorticoid receptor inhibits transforming growth factor-beta signaling by directly targeting the transcriptional activation function of Smad3.
C. Song (1999)
Transforming Growth Factor-β1 Inhibition of Vascular Smooth Muscle Cell Activation Is Mediated via Smad3*
M. Feinberg (2004)

This paper is referenced by
Suppression of prolactin signaling by pyrrolidine dithiocarbamate is alleviated by N-acetylcysteine in mammary epithelial cells.
Jen-Hsing Wang (2014)
A corn straw-based diet increases release of inflammatory cytokines in peripheral blood mononuclear cells of dairy cows
Yan-yi Che (2018)
Tif1γ is essential for the terminal differentiation of mammary alveolar epithelial cells and for lactation through SMAD4 inhibition
C. Hesling (2013)
Tif 1 is essential for the terminal differentiation of mammary alveolar epithelial cells and for lactation through SMAD 4 inhibition
C. Hesling (2012)
This information is current as Cell and Langerhans Cell Development Human CD 34-Derived Interstitial Dendritic Tight Control of STAT 5 Activity Determines
M. Woltman (2011)
Paracrine control of milk protein gene expression in tammar wallaby
Stephen S Wanyonyi (2013)
Perinatal exposure to xenoestrogens impairs mammary gland differentiation and modifies milk composition in Wistar rats.
L. Kass (2012)
Extracellular Matrix Composition Reveals Complex and Dynamic Stromal-Epithelial Interactions in the Mammary Gland
O. Maller (2010)
Proprotein convertase FURIN regulates T cell receptor‐induced transactivation
Z. Ortutay (2015)
Transforming growth factor β signaling regulates the invasiveness of normal mammary epithelial cells and the metastasis formation of tumor cells
V. Vafaizadeh (2012)
Signal transducer and activator of transcription 5 as a key signaling pathway in normal mammary gland developmental biology and breast cancer
P. Furth (2011)
Tight Control of STAT5 Activity Determines Human CD34-Derived Interstitial Dendritic Cell and Langerhans Cell Development
L. van de Laar (2011)
Transcriptome analysis of mammary epithelial cell gene expression reveals novel roles of the extracellular matrix
S. Wanyonyi (2017)
Semantic Scholar Logo Some data provided by SemanticScholar