scholarly journals Identification of AKT-regulated genes in inducible MERAkt cells

2001 ◽  
Vol 7 (2) ◽  
pp. 105-114 ◽  
Author(s):  
IRENE KUHN ◽  
MARTY F. BARTHOLDI ◽  
HUGH SALAMON ◽  
RICHARD I. FELDMAN ◽  
RICHARD A. ROTH ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Cdna Array ◽  
Signal Transduction Pathway ◽  
Transforming Growth Factor Β ◽  
Oncogenic Transformation ◽  
Nih3t3 Cells ◽  
Estrogen Receptor Ligands ◽  
Phosphoinositide 3 Kinase

AKT/protein kinase B plays a critical role in the phosphoinositide 3-kinase (PI3-kinase) pathway regulating cell growth, differentiation, and oncogenic transformation. Akt1-regulated genes were identified by cDNA array hybridization analysis using an inducible AKT1 protein, MERAKT. Treatment of MERAkt cells with estrogen receptor ligands resulted in phosphorylative activation of MERAKT. Genes differentially expressed in MERAkt/NIH3T3 cells treated with tamoxifen, raloxifene, ICI-182780, and ZK955, were identified at 3 and 20 h. AKT activation resulted in the repression of c-myc, early growth response 1 (EGR1), transforming growth factor β receptor III (TGF-βr III), and thrombospondin-1 (THBS1). Although c-myc induction is often associated with oncogenic transformation, the c-myc repression observed here is consistent with the anti-apoptotic function of AKT. Repression of THBS1 and EGR1 is consistent with the known pro-angiogenic functions of AKT. AKT-regulated genes were found to be largely distinct from platelet-derived growth factor-β (PDGFβ)-regulated genes; only T-cell death-associated gene 51 (TDAG51) was induced in both cases. In contrast to their repression by AKT, c-myc, THBS1, and EGR1 were induced by PDGFβ, indicating negative interference between elements upstream and downstream of AKT1 in the PDGFβ signal transduction pathway.

scholarly journals A Functional Connection between pRB and Transforming Growth Factor β in Growth Inhibition and Mammary Gland Development

2009 ◽  
Vol 29 (16) ◽  
pp. 4455-4466 ◽  
Author(s):  
Sarah M. Francis ◽  
Jacqueline Bergsied ◽  
Christian E. Isaac ◽  
Courtney H. Coschi ◽  
Alison L. Martens ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Growth Factor ◽  
Growth Inhibition ◽  
Mammary Gland Development ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Mammary Development ◽  
Functional Connection ◽  
Gland Development

ABSTRACT Transforming growth factor β (TGF-β) is a crucial mediator of breast development, and loss of TGF-β-induced growth arrest is a hallmark of breast cancer. TGF-β has been shown to inhibit cyclin-dependent kinase (CDK) activity, which leads to the accumulation of hypophosphorylated pRB. However, unlike other components of TGF-β cytostatic signaling, pRB is thought to be dispensable for mammary development. Using gene-targeted mice carrying subtle missense changes in pRB (Rb1 ΔL and Rb1NF ), we have discovered that pRB plays a critical role in mammary gland development. In particular, Rb1 mutant female mice have hyperplastic mammary epithelium and defects in nursing due to insensitivity to TGF-β growth inhibition. In contrast with previous studies that highlighted the inhibition of cyclin/CDK activity by TGF-β signaling, our experiments revealed that active transcriptional repression of E2F target genes by pRB downstream of CDKs is also a key component of TGF-β cytostatic signaling. Taken together, our work demonstrates a unique functional connection between pRB and TGF-β in growth control and mammary gland development.

scholarly journals Local versus systemic control of bone and skeletal muscle mass by components of the transforming growth factor-β signaling pathway

2021 ◽  
Vol 118 (33) ◽  
pp. e2111401118
Author(s):  
Yewei Liu ◽  
Adam Lehar ◽  
Renata Rydzik ◽  
Harshpreet Chandok ◽  
Yun-Sil Lee ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Muscle Mass ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
The Body ◽  
Dependent Manner ◽  
Bone Homeostasis ◽  
Mineral Density

Skeletal muscle and bone homeostasis are regulated by members of the myostatin/GDF-11/activin branch of the transforming growth factor-β superfamily, which share many regulatory components, including inhibitory extracellular binding proteins and receptors that mediate signaling. Here, we present the results of genetic studies demonstrating a critical role for the binding protein follistatin (FST) in regulating both skeletal muscle and bone. Using an allelic series corresponding to varying expression levels of endogenous Fst, we show that FST acts in an exquisitely dose-dependent manner to regulate both muscle mass and bone density. Moreover, by employing a genetic strategy to target Fst expression only in the posterior (caudal) region of the animal, we show that the effects of Fst loss are mostly restricted to the posterior region, implying that locally produced FST plays a much more important role than circulating FST with respect to regulation of muscle and bone. Finally, we show that targeting receptors for these ligands specifically in osteoblasts leads to dramatic increases in bone mass, with trabecular bone volume fraction being increased by 12- to 13-fold and bone mineral density being increased by 8- to 9-fold in humeri, femurs, and lumbar vertebrae. These findings demonstrate that bone, like muscle, has an enormous inherent capacity for growth that is normally kept in check by this signaling system and suggest that the extent to which this regulatory mechanism may be used throughout the body to regulate tissue mass may be more significant than previously appreciated.

scholarly journals Transforming Growth Factor β/Smad3 Signaling Regulates IRF-7 Function and Transcriptional Activation of the Beta Interferon Promoter

2004 ◽  
Vol 24 (3) ◽  
pp. 1411-1425 ◽  
Author(s):  
Jing Qing ◽  
Cheng Liu ◽  
Lisa Choy ◽  
Rui-Yun Wu ◽  
Joseph S. Pagano ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transcriptional Activation ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Dominant Negative ◽  
Negative Interference ◽  
Rapid Induction ◽  
Dominant Negative Interference ◽  
Smad3 Expression

ABSTRACT The rapid induction of alpha interferon (IFN-α) and IFN-β expression plays a critical role in the innate immune response against viral infection. We studied the effects of transforming growth factor β (TGF-β) and its intracellular effectors, the Smads, on the function of IRF-7, an essential transcription factor for IFN-α and -β induction. IRF-7 interacted with Smads, and IRF-7, but not IRF-3, cooperated with Smad3 to activate IFN-β transcription. This transcriptional cooperation occurred at the IRF-binding sequences in the IFN-β promoter, and dominant-negative interference with TGF-β receptor signaling and Smad3 function decreased IRF-7-mediated transcription. Furthermore, elimination of Smad3 expression in Smad3−/− fibroblasts delayed and decreased double-stranded RNA-induced expression of endogenous IFN-β, whereas restoration of Smad3 expression enhanced IFN-β induction. The IRF-7-Smad3 cooperativity resulted from the regulation of the transactivation activity of IRF-7 by Smad3, and dominant-negative interference with Smad3 function decreased IRF-7 activity. Consistent with the regulation by Smad3, the transcriptional activity of IRF-7 depended on and was regulated by TGF-β signaling. Our studies underscore a role of TGF-β/Smad3 signaling in IRF-7-mediated induction of IFN-β expression.

scholarly journals α1B-Adrenergic receptor phosphorylation and desensitization induced by transforming growth factor-β

2002 ◽  
Vol 368 (2) ◽  
pp. 581-587 ◽  
Author(s):  
M. Teresa ROMERO-ÁVILA ◽  
C. Fabián FLORES-JASSO ◽  
J. Adolfo GARCÍA-SÁINZ
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Receptor Phosphorylation ◽  
Kinase C ◽  
Phosphoinositide 3 Kinase

Transforming growth factor-β (TGF-β) induced α1B-adrenergic receptor phosphorylation in Rat-1 fibroblasts stably expressing these adrenoceptors. This effect of TGF-β was rapid, reaching a maximum within 30min and decreasing thereafter, and concentration-dependent (EC50 0.3pM). The phosphoinositide 3-kinase inhibitors wortmannin and LY294002, and the protein kinase C inhibitors staurosporine, Ro 318220 and bisindolylmaleimide, blocked the effect of this growth factor. α1B-Adrenergic receptor phosphorylation was associated with desensitization, as indicated by a reduction in the adrenergic-mediated production of [3H]inositol phosphates. Phosphorylation of α1B-adrenergic receptors by TGF-β was also observed in Cos-1 cells transfected with the receptor. Co-transfection of the dominant-negative mutant of the regulatory subunit of phosphoinositide 3-kinase (Δp85) inhibited the phosphorylation of α1B-adrenergic receptors induced by TGF-β. Our results indicate that activation of TGF-β receptors induces α1B-adrenergic receptor phosphorylation and desensitization. The data suggest that phosphoinositide 3-kinase and protein kinase C play key roles in this effect of TGF-β.

scholarly journals Critical Role of Smads and AP-1 Complex in Transforming Growth Factor-β-dependent Apoptosis

2000 ◽  
Vol 275 (46) ◽  
pp. 36295-36302 ◽  
Author(s):  
Yasuko Yamamura ◽  
Xianxin Hua ◽  
Svetlana Bergelson ◽  
Harvey F. Lodish
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β

Transforming growth factor-β-regulated expression of genes in macrophages implicated in the control of cholesterol homoeostasis

2006 ◽  
Vol 34 (6) ◽  
pp. 1141-1144 ◽  
Author(s):  
D.P. Ramji ◽  
N.N. Singh ◽  
P. Foka ◽  
S.A. Irvine ◽  
K. Arnaoutakis
Keyword(s):  
Growth Factor ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Crucial Importance ◽  
Expression Of Genes ◽  
Regulated Expression ◽  
Key Genes

The regulation of macrophage cholesterol homoeostasis is of crucial importance in the pathogenesis of atherosclerosis, an underlying cause of heart attack and stroke. Several recent studies have revealed a critical role for the cytokine TGF-β (transforming growth factor-β), a key regulator of the immune and inflammatory responses, in atherogenesis. We discuss here the TGF-β signalling pathway and its role in this disease along with the outcome of our recent studies on the action of the cytokine on the expression of key genes implicated in the uptake or efflux of cholesterol by macrophages and the molecular mechanisms underlying such regulation.

Myostatin-null mice exhibit delayed skin wound healing through the blockade of transforming growth factor-β signaling by decorin

2012 ◽  
Vol 302 (8) ◽  
pp. C1213-C1225 ◽  
Author(s):  
Chen Zhang ◽  
Chek Kun Tan ◽  
Craig McFarlane ◽  
Mridula Sharma ◽  
Nguan Soon Tan ◽  
...  
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Wound Repair ◽  
Transforming Growth Factor ◽  
Healing Process ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Skin Wound ◽  
Wound Healing Process ◽  
Skin Wound Healing

Myostatin (Mstn) is a secreted growth and differentiation factor that belongs to the transforming growth factor-β (TGF-β) superfamily. Mstn has been well characterized as a regulator of myogenesis and has been shown to play a critical role in postnatal muscle regeneration. Herein, we report for the first time that Mstn is expressed in both epidermis and dermis of murine and human skin and that Mstn-null mice exhibited delayed skin wound healing attributable to a combination of effects resulting from delayed epidermal reepithelialization and dermal contraction. In epidermis, reduced keratinocyte migration and protracted keratinocyte proliferation were observed, which subsequently led to delayed recovery of epidermal thickness and slower reepithelialization. Furthermore, primary keratinocytes derived from Mstn-null mice displayed reduced migration capacity and increased proliferation rate as assessed through in vitro migration and adhesion assays, as well as bromodeoxyuridine incorporation and Western blot analysis. Moreover, in dermis, both fibroblast-to-myofibroblast transformation and collagen deposition were concomitantly reduced, resulting in a delayed dermal wound contraction. These decreases are due to the inhibition of TGF-β signaling. In agreement, the expression of decorin, a naturally occurring TGF-β suppressor, was elevated in Mstn-null mice; moreover, topical treatment with TGF-β1 protein rescued the impaired skin wound healing observed in Mstn-null mice. These observations highlight the interplay between TGF-β and Mstn signaling pathways, specifically through Mstn regulation of decorin levels during the skin wound healing process. Thus we propose that Mstn agonists might be beneficial for skin wound repair.

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