Characterization of transforming growth factor‐β growth regulatory effects and receptors on bovine mammary cells

Woodward, Terry L.; Dumont, Nancy; O’Connor-McCourt, Maureen D.; Turner, Jeffrey D.; Philip, Anie

doi:10.1002/jcp.1041650215

Cited by 33 publications

(29 citation statements)

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“…Others have also shown that the TGF␤ receptors are under autoregulation control by ligand stimulation (18). It has been previously shown that treatment with TGF␤1 leads to down-regulation of TGF␤RII levels (19).…”

Section: Discussionmentioning

confidence: 98%

Silencing of the Transforming Growth Factor-β (TGFβ) Receptor II by Krüppel-like Factor 14 Underscores the Importance of a Negative Feedback Mechanism in TGFβ Signaling

Truty

Lomberk²,

Fernández-Zapico³

et al. 2009

Journal of Biological Chemistry

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The role of non-Smad proteins in the regulation of transforming growth factor-␤ (TGF␤) signaling is an emerging line of active investigation. Here, we characterize the role of KLF14, as a TGF␤-inducible, non-Smad protein that silences the TGF␤ receptor II (TGF␤RII) promoter. Together with endocytosis, transcriptional silencing is a critical mechanism for down-regulating TGF␤ receptors at the cell surface. However, the mechanisms underlying transcriptional repression of these receptors remain poorly understood. KLF14 has been chosen from a comprehensive screen of 24 members of the Sp/KLF family due to its TGF␤ inducibility, its ability to regulate the TGF␤RII promoter, and the fact that this protein had yet to be functionally characterized. We find that KLF14 represses the TGF␤RII, a function that is augmented by TGF␤ treatment. Mapping of the TGF␤RII promoter, in combination with site-directed mutagenesis, electromobility shift, and chromatin immunoprecipitation assays, have identified distinct GC-rich sequences used by KLF14 to regulate this promoter. Mechanistically, KLF14 represses the TGF␤RII promoter via a co-repressor complex containing mSin3A and HDAC2. Furthermore, the TGF␤ pathway activation leads to recruitment of a KLF14-mSin3A-HDAC2 repressor complex to the TGF␤RII promoter, as well as the remodeling of chromatin to increase histone marks that associate with transcriptional silencing. Thus, these results describe a novel negative-feedback mechanism by which TGF␤RII activation at the cell surface induces the expression of KLF14 to ultimately silence the TGF␤RII and further expand the network of non-Smad transcription factors that participate in the TGF␤ pathway.The family of cytokines composed of TGF␤, 4 bone morphogenetic proteins, activins, inhibins, connective tissue growth factors (CCN family), along with their corresponding signaling molecules, are master regulators of normal homeostasis and development (1-10). Consequently, alterations in these pathways lead to severe malformations and diseases, including cancer. TGF␤ is the best characterized pathway within this family of cytokines. Recent studies reveal, for instance, the existence of two types of membrane-to-nucleus TGF␤ signaling mechanisms, namely the Smad-dependent and non-Smad proteinmediated cascades, although evidence of cross-talk between these two cascades is also emerging (4, 9). Therefore, even though our understanding of the complexity underlying TGF␤ signaling continues to grow, classification into these two types of mechanisms has helped to organize the nascent theoretical framework for advancing this field of research by the integration of new findings into easily understandable paradigms.The canonical Smad-mediated TGF␤ pathway is activated by binding of TGF␤1, -2, and/or -3 cytokines to the TGF␤RII, which then dimerizes with and activates the TGF␤ receptor I through serine phosphorylation of the regulatory GS-domain. The Type I receptor, in turn, phosphorylates receptor-bound Smad (Smad2/3) at the C-terminal SXS motif, releasi...

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Section: Discussionmentioning

confidence: 98%

Silencing of the Transforming Growth Factor-β (TGFβ) Receptor II by Krüppel-like Factor 14 Underscores the Importance of a Negative Feedback Mechanism in TGFβ Signaling

Truty

Lomberk²,

Fernández-Zapico³

et al. 2009

Journal of Biological Chemistry

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“…TGFb1 has been shown to inhibit bovine mammary epithelial cell proliferation (Woodward et al 1995, Purup et al 2000a.…”

Section: Discussionmentioning

confidence: 99%

“…4). We also measured TGFb1 expression because it is increased in the serum of rapidly growing heifers and has been shown to inhibit MAC-T and pMEC proliferation (Woodward et al 1995, Purup et al 2000a. TGFb1 expression was not affected by development or nutrition (Fig.…”

Section: Effects Of Development and Nutrition On Mfp Production Of Irmentioning

confidence: 99%

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Regulation of mammary parenchymal growth by the fat pad in prepubertal dairy heifers: role of inflammation-related proteins

Thorn¹,

Purup²,

Vestergaard³

et al. 2007

Journal of Endocrinology

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In prepubertal heifers, the mammary parenchyma consists of epithelial and myoepithelial cells growing within a mammary fat pad (MFP). The MFP produces IGF-I that stimulates epithelial cell proliferation. In other species, adipose tissue expansion induces inflammation-related proteins (IRP), such as tumor necrosis factor a (TNFa), interleukin (IL)-6, IL-1b transforming growth factor b, monocyte chemoattractant protein 1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1). The MFP production of IRP may influence mammary development because they impair not only insulin but also IGF-I actions. Moreover, the MFP expansion seen with development and increased nutrition coincides with reduced parenchymal growth. Our first objective was to identify IRP capable of altering proliferation of bovine mammary epithelial cells. TNFa, but neither IL-6, IL-1b MCP-1 nor PAI-1, inhibited basal and IGF-I-stimulated proliferation in MAC-T cells and primary cells isolated from heifers. Our second objective was to determine whether MFP expression of IRP changed in a manner consistent with inhibition of parenchymal growth. MFP expression was measured from 100 to 350 kg body weight (experiment 1) or at 240 kg body weight (experiment 2) in dairy heifers offered restricted or high planes of nutrition. In experiment 1, neither nutrition nor development altered MFP expression of TNFa. Nutrition increased MCP-1 and PAI-1 but only before MFP expansion and after cessation of allometric parenchymal growth. In experiment 2, nutrition increased TNFa and PAI-1, but not MCP-1. Thus, MFP expansion increases IRP production in cattle, but this is unlikely to contribute to reduced parenchymal growth observed with development or increased nutrition.

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“…The use of growth factors, such as TGF-P and PDGF-AB, to stimulate fibroblast proliferation and protein synthesis in vitro has been studied previously for ligament cells [9,30]. A significant difference between the two TGF-P isoforms (TGF-PI and TGF-P2) has not been demonstrated in adult cells [5,31]. As we had previously shown TGF-P2 to result in formation of a larger scar mass and increased type I collagen production with an in vivo MCL model [28], this isoform was selected for this continuing study of delivery method, dose-dependence, and interaction with…”

Section: Introductionmentioning

confidence: 99%

The biomechanical response to doses of TGF‐β2 in the healing rabbit medial collateral ligament

Spindler

Murray

Detwiler

et al. 2003

Journal Orthopaedic Research

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Ligament injuries result in significant disability in over 100,000 patients each year. Despite current methods of treatment, 13% of patients with medial collateral ligament (MCL) injury develop early signs of arthritis, suggesting an incomplete return of knee stability. The principal hypothesis of this work was that the addition of TGF-PZ to the healing MCL would accelerate the development of scar strength and stiffness. Forty-four rabbits were divided evenly into four groups, with each group receiving either 0.1, 1 or 5 pg of TGF-02 and the fourth group receiving 1 pg TGF-P2 and 1 pg of PDGF. Each rabbit underwent bilateral transection of the MCL, with one side having treatment with one of four doses of growth factor and the other side left untreated. All animals were sacrificed at 6 weeks and the structural properties of maximum load at failure, stiffness, and energy absorbed at failure measured. All treatment groups demonstrated an increase in scar mass, but no group had a significant increase in scar load at ,/uilure at 6 weeks. The addition of 0.1 pg TGF-02 led to a significant increase in scar stiffness. The addition of PDGF had no significant effect on any of the parameters studied. This study suggests the mechanical stiffness, but not the load at failure, of ligament scar can be significantly altered by the administration of TGF-P2.

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Characterization of transforming growth factor‐β growth regulatory effects and receptors on bovine mammary cells

Cited by 33 publications

References 50 publications

Silencing of the Transforming Growth Factor-β (TGFβ) Receptor II by Krüppel-like Factor 14 Underscores the Importance of a Negative Feedback Mechanism in TGFβ Signaling

Silencing of the Transforming Growth Factor-β (TGFβ) Receptor II by Krüppel-like Factor 14 Underscores the Importance of a Negative Feedback Mechanism in TGFβ Signaling

Regulation of mammary parenchymal growth by the fat pad in prepubertal dairy heifers: role of inflammation-related proteins

The biomechanical response to doses of TGF‐β2 in the healing rabbit medial collateral ligament

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