Prolactin signals via Stat5 and Oct-1 to the proximal cyclin D1 promoter

Brockman, Jennifer L.; Schuler, Linda A.

doi:10.1016/j.mce.2005.04.006

Cited by 50 publications

(45 citation statements)

References 39 publications

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“…Cyclin D1 is an important regulator of lobuloalveolar development, as illustrated by the phenotype of the cyclin D1 knock-out mice that fail to undergo proper lobuloalveolar formation during pregnancy (61), a phenotype shared by PRL and PRLR knock-out mice (62,63). This is consistent with the fact PRL regulates cyclin D1 gene promoter through STAT5 signaling (64). The antagonistic effect of activin/TGF␤ on lactogenic hormone induction of cyclin D1 implicates that they play a regulatory role in mammary gland development and allows for the differentiation phase of late pregnancy to occur by regulating proliferation of the lobuloalveoli.…”

Section: Discussionmentioning

confidence: 52%

Smad Signaling Antagonizes STAT5-mediated Gene Transcription and Mammary Epithelial Cell Differentiation

Cocolakis

Dai

Drevet

et al. 2008

Journal of Biological Chemistry

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Both the transforming growth factor-␤ (TGF␤)/Smad and the prolactin/JAK/STAT pathway are critical to the proper development, maintenance, and function of the mammary epithelial tissue. Interestingly, opposing physiological effects between these two signaling pathways are prominent in the regulation of mammary gland development. However, the exact nature of the biological network existing between the Smad and STAT signal transduction pathways has remained elusive. We identified a novel regulatory cross-talk mechanism by which TGF␤-induced Smad signaling acts to antagonize prolactin-mediated JAK/ STAT signaling and expression of target genes. Furthermore, we found activin, another member of the TGF␤ family, to also efficiently block STAT5 signaling and ␤-casein expression in mammary epithelial cells. Our results indicate that ligand-induced activation of Smad2, -3, and -4 by activin and TGF␤ leads to a direct inhibition of STAT5 transactivation and STAT5-mediated transcription of the downstream target genes, ␤-casein and cyclin D1, thereby blocking vital processes for mammary gland growth and differentiation. Finally, we unveiled the mechanism by which these two signaling cascades antagonize their effects, and we found that activated Smads inhibit STAT5 association with its co-activator CREB-binding protein, thus blocking STAT5 transactivation of its target genes and leading to inhibition of mammary gland differentiation and lactation.Mammary gland growth and differentiation are complex processes regulated by steroids, polypeptide hormones, and growth factors. Among them, prolactin and TGF␤ 5 family members play a major role in the regulation of mammary gland development. Prolactin is required for lobuloalveolar formation and functional differentiation of mammary epithelial cells.TGF␤ has an opposite effect, inducing apoptosis during mammary gland involution and inhibiting expression of the milk proteins (1, 2). TGF␤ is expressed and plays critical roles in every phase of post-natal mammary gland development (3). TGF␤ has been shown to inhibit alveolar formation and synthesis of milk proteins and to induce apoptosis during involution of the mammary gland (4 -6). Together, these data suggest that TGF␤ would antagonize prolactin (PRL)-induced signals in mammary cells (7,8). The effect of activin, another member of the TGF␤ family, on the development of the mammary gland stems from the activin ␤b subunit knock-out mouse model. Deletion of the activin ␤b subunit, through ablation of three of the dimeric ␤ molecules (activin B, activin AB, and inhibin B), results in mice with the phenotype of incomplete mammary development and an absence of lactation, suggesting that activin/inhibin may play an important role in this process (9). In summary, although TGF␤ and activin clearly play important roles in mammary gland development, their mechanism of action in mammary epithelial functional differentiation has yet to be fully elucidated.Prolactin signal transduction is induced by formation of a homodimeric complex of two molec...

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Section: Discussionmentioning

confidence: 52%

Smad Signaling Antagonizes STAT5-mediated Gene Transcription and Mammary Epithelial Cell Differentiation

Cocolakis

Dai

Drevet

et al. 2008

Journal of Biological Chemistry

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“…The ability of Oct-1 to regulate expression of proteins involved in cell cycle regulation (3,10,27), apoptosis (16,22), and immunity (5,12,17,18,33,34,36,58) and Oct-1 activation in response to stress signals (16,22,41,60), including viral infection (1), suggest an important role for Oct-1 in a defense mechanism against cellular stress. Accordingly, here we show that Oct-1-deficient MEFs exhibit increased endogenous IFN-A gene expression and modification in the pattern of IFN-A subtypes after virus induction.…”

Section: Vol 25 2005 Oct-1 Represses Ifn-a Gene Expression After Inmentioning

confidence: 99%

The POU Transcription Factor Oct-1 Represses Virus-Induced Interferon A Gene Expression

Mésplède¹,

Island²,

Christeff³

et al. 2005

Molecular and Cellular Biology

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Alpha interferon (IFN-␣Alpha interferon (IFN-␣) and IFN-␤ are able to interfere with viral infection. They exert a vast array of biologic functions, including growth arrest, cell differentiation, and immune system regulation (for reviews, see references 28 and 51). This regulation extends from innate immunity to cellular and humoral adaptive immune responses. A strict control of expression is needed to prevent detrimental effects of unregulated IFN. IFN transcription is coordinately induced in human and mouse cells infected by virus. Multiple IFN-A subtypes exhibit differences in expression of their individual mRNAs.IFN-A transcription is regulated by a number of different activators and repressors. Among these factors, the interferon regulatory factors (IRFs) play an important role in the stimulation of cellular antiviral defense mechanisms in different cell types. IRFs regulate transcription by interacting with gene promoter sequences. Until now, repressors involved in negative regulation of the IFN-A genes have not been well characterized (for a review, see reference 29). We have shown that in addition to substitutions in proximal virus responsive element A (VRE-A) (2), the low expression levels of the IFN-A11 and IFN-A5 genes after virus induction are also due to the presence of a distal negative regulatory element (DNRE) of 20 bp, which is delimited upstream of VRE-A (20, 25, 26). The analysis of the DNRE responsible for the virus-induced transcription repression of some IFN-A promoters led us to study the homeodomain transcription factor Pitx1 (25). Upon virus induction, Pitx1 negatively regulates the transcription of DNREcontaining IFN-A11 and IFN-A5 promoters (20,25). We have recently shown that Pitx1 inhibits the IRF-3 and IRF-7 transcription activation of the IFN-A11 and IFN-A5 promoters and interacts physically with .Here we show that the POU protein Oct-1 binds in vitro to the DNRE and in vivo to the endogenous IFN-A11 promoter in mock-induced and induced cells. Furthermore, Oct-1 represses IFN-A11 expression upon IRF overexpression. Moreover, we show that Oct-1-deficient MEFs exhibit increased in vivo IFN-A gene expression and increased antiviral activity. Finally, the IFN-A expression pattern is modified in Oct-1-deficient MEFs. The broad representation of effective and potent octamer-like sequences within IFN-A promoters suggests an important role for Oct-1 in IFN-A regulation. We suggest this could have implications in IFN-␣-based combinatorial therapies. MATERIALS AND METHODSDNA transfection, viral induction, and transfection assays. Murine L929 cells were transfected by the standard calcium phosphate precipitation method as previously described (26). Newcastle disease virus (NDV) induction was carried out 24 h later. The mock-induced cells were set up as described above except that no NDV was added. Cells were harvested 24 h postinduction, and cytoplasm extracts were prepared. Luciferase activity was measured in cell lysates by using commercial reagents (Promega). Transfection efficiency was de...

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“…Our results on T47D cell number are therefore consistent with the hypothesis that the increased LF to SF1b ratio may contribute to tumor growth or tumor cell survival. Antagonism of signaling through the LF, either by LF-SF1b heterodimerization or by down-regulation of LF expression, could counteract unmodified PRLstimulated promotion of the cell cycle (Brockman & Schuler 2005) or anti-apoptotic signaling (LaVoie & Witorsch 1995, Peierce & Chen 2004. The source of this PRL could be either endocrine or autocrine (Ben-Jonathan et al 2002), or both.…”

Section: Discussionmentioning

confidence: 99%

“…A b-casein-Luc plasmid, which contains 2 . 4 kb of the b-casein promoter upstream of a luciferase reporter gene (Lee et al 1989, Brockman & Schuler 2005, was a generous gift from Dr Linda Schuler (Madison, WI, USA) and Jeffrey Rosen (Baylor, TX, USA). The cell number assay reagents (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), inner salt) and phenazine methosulfate (PMS) were products of Promega.…”

Section: Methodsmentioning

confidence: 99%

Short form 1b human prolactin receptor down-regulates expression of the long form

Tan¹,

Walker²

2009

Journal of Molecular Endocrinology

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Alternative splicing produces different human prolactin (PRL) receptors. These include a long form (LF) and two short forms (SF1a and SF1b). The SFs of the receptor can act as dominant negatives for PRL effector function through the LF. This is proposed to be due to LF-SF heterodimerization and resultant interference with LF-LF dimer signaling. We, along with others, have provided evidence for LF-SF heterodimerization of the human receptors in support of this mechanism, along with others. However, to further investigate the ways SF may influence LF function, we co-transfected human embryonic kidney 293 cells with vectors coding for tagged (green fluorescent protein (GFP) or luciferase) LF alone or plus untagged SF1b and measured LF-GFP intensity, LF-luciferase activity, and LF mRNA 48 h later. Equal amounts of SF1b cDNA decreased LF-GFP fluorescence intensity, LF-luciferase activity, and LF mRNA by 80-100%. Similar co-transfections with untagged LF had no significant effect on tagged LF expression. Use of hygromycin showed degradation of already formed protein was the same for LF-luciferase alone and LF-luciferase with SF1b. Inhibition of mRNA synthesis, on the other hand, showed that SF1b expression accelerated LF mRNA degradation two-to three-fold. SF1b also down-regulated expression of endogenous LF mRNA in T47D breast cancer cells and opposed an increase in cell number resulting from transfection with extra LF alone. These results demonstrate a previously unrecognized mechanism whereby SF1b affects the end result of signaling through the LF receptor. The effects on cell number also support the concept that the LF:SF1b ratio may be relevant to tumor growth.

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Prolactin signals via Stat5 and Oct-1 to the proximal cyclin D1 promoter

Cited by 50 publications

References 39 publications

Smad Signaling Antagonizes STAT5-mediated Gene Transcription and Mammary Epithelial Cell Differentiation

Smad Signaling Antagonizes STAT5-mediated Gene Transcription and Mammary Epithelial Cell Differentiation

The POU Transcription Factor Oct-1 Represses Virus-Induced Interferon A Gene Expression

Short form 1b human prolactin receptor down-regulates expression of the long form

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