Smad3 and Pitx2 cooperate in stimulation of FSHβ gene transcription

Suszko, Magdalena I.; Antenos, Monica; Balkin, Daniel M.; Woodruff, Teresa K.

doi:10.1016/j.mce.2007.10.003

Cited by 21 publications

(13 citation statements)

References 46 publications

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“…PITX1/2 and SMAD proteins physically interact and cooperatively activate the Fshb promoter. Moreover, depletion of endogenous PITX proteins impairs activin-stimulated Fshb transcription in L␤T2 cells (35,37,50,52). Nevertheless, it is presently unclear whether or how functional PITX/SMAD complexes are formed on the Fshb promoter as there are no SBEs in immediate proximity to the PITX-binding site.…”

Section: Activin Induction Of Fshb Transcriptionmentioning

confidence: 99%

Minireview: Activin Signaling in Gonadotropes: What Does the FOX say… to the SMAD?

Fortin

Ongaro

et al. 2015

Molecular Endocrinology

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The activins were discovered and named based on their abilities to stimulate FSH secretion and FSHβ (Fshb) subunit expression by pituitary gonadotrope cells. According to subsequent in vitro observations, activins also stimulate the transcription of the GnRH receptor (Gnrhr) and the activin antagonist, follistatin (Fst). Thus, not only do activins stimulate FSH directly, they have the potential to regulate both FSH and LH indirectly by modulating gonadotrope sensitivity to hypothalamic GnRH. Moreover, activins may negatively regulate their own actions by stimulating the production of one of their principal antagonists. Here, we describe our current understanding of the mechanisms through which activins regulate Fshb, Gnrhr, and Fst transcription in vitro. The activin signaling molecules SMAD3 and SMAD4 appear to partner with the winged-helix/forkhead transcription factor, forkhead box L2 (FOXL2), to regulate expression of all 3 genes. However, in vivo data paint a different picture. Although conditional deletion of Foxl2 and/or Smad4 in murine gonadotropes produces impairments in FSH synthesis and secretion as well as in pituitary Fst expression, Gnrhr mRNA levels are either unperturbed or increased in these animals. Surprisingly, gonadotrope-specific deletion of Smad3 alone or with Smad2 does not impair FSH production or fertility; however, mice harboring these mutations may express a DNA binding-deficient, but otherwise functional, SMAD3 protein. Collectively, the available data firmly establish roles for FOXL2 and SMAD4 in Fshb and Fst expression in gonadotrope cells, whereas SMAD3's role requires further investigation. Gnrhr expression, in contrast, appears to be FOXL2, SMAD4, and, perhaps, activin independent in vivo.

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Section: Activin Induction Of Fshb Transcriptionmentioning

confidence: 99%

Minireview: Activin Signaling in Gonadotropes: What Does the FOX say… to the SMAD?

Fortin

Ongaro

et al. 2015

Molecular Endocrinology

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“…Overexpression of PITX2C in heterologous cells confers activin induction to the rat promoter, but this is not observed with a murine reporter under similar experimental conditions (136,138). PITX1 and -2 proteins can physically interact with SMAD3 and perhaps SMADs 2 and 4 (136,137,216). These data suggest that SMADs and PITX proteins interact to regulate Fshb promoter activity; however, given the $60 bp separating the PITX site and closest minimal SBE (Fig.…”

Section: Smad-binding Elements (Sbe) In the Fshb Promotermentioning

confidence: 89%

“…These mutations similarly inhibit SMAD2/3/4 stimulation of the murine promoter (136). Depletion of endogenous PITX1 and/or PITX2 levels inhibits basal and/or activin A-induced activity of murine and rat reporters (136,137). Dominant-negative PITX1 or -2 proteins produce similar antagonistic effects on the murine promoter.…”

Section: Smad-binding Elements (Sbe) In the Fshb Promotermentioning

confidence: 93%

“…PITX1 is broadly expressed in different anterior pituitary cell types and has been argued to function as a panpituitary regulator of cell-specific gene transcription (131,134,135). Overexpression of PITX1 or the related PITX2 (various isoforms) stimulates rat, murine, and human Fshb/FSHB promoter-reporter activities in heterologous cells, and knockdown of the endogenous proteins with specific short interfering RNA molecules (siRNA) attenuates both basal and activin A-regulated transcription in LbT2 cells (129,131,(136)(137)(138)(139); see the section ''How do hormones turn FSH synthesis on (and off)? Activin regulation of Fshb'').…”

Section: Gonadotrope-specific Expression Of Fshbmentioning

confidence: 99%

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Mechanisms of FSH synthesis: what we know, what we don't, and why you should care

Bernard

Fortin

Wang

et al. 2010

Fertility and Sterility

132

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“…PITX2 represents an important transcription factor responsible for the development of body symmetry [142]. It is involved in the TGF-b, hedgehog [143] and retinoic acid receptor [144] signaling pathways, and is activated by b-catenin [145][146][147] or SMAD signaling complexes [148][149][150][151][152], which regulate transcription of procollagen lysyl hydroxylase [153] and interact with YB-1 [154]. In breast cancer, PITX2 methylation status constitutes a prognostic factor to predict diseasefree and overall survival in untreated breast cancer patients, but also in patients treated with tamoxifen-or anthracycline-containing chemotherapy regimens [138][139][140][141].…”

Section: Epigenetically Regulated Cancer Genes: a Rich Source Of Breamentioning

confidence: 99%

Emerging Biomarkers in Breast Cancer Care

2010

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Currently, decision-making for breast cancer treatment in the clinical setting is mainly based on clinical data, histomorphological features of the tumor tissue and a few cancer biomarkers such as steroid hormone receptor status (estrogen and progesterone receptors) and oncoprotein HER2 status. Although various therapeutic options were introduced into the clinic in recent decades, with the objective of improving surgery, radiotherapy, biochemotherapy and chemotherapy, varying response of individual patients to certain types of therapy and therapy resistance is still a challenge in breast cancer care. Therefore, since breast cancer treatment should be based on individual features of the patient and her tumor, tailored therapy should be an option by integrating cancer biomarkers to define patients at risk and to reliably predict their course of the disease and/or response to cancer therapy. Recently, candidate-marker approaches and genome-wide transcriptomic and epigenetic screening of different breast cancer tissues and bodily fluids resulted in new promising biomarker panels, allowing breast cancer prognosis, prediction of therapy response and monitoring of therapy efficacy. These biomarkers are now subject of validation in prospective clinical trials.

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Smad3 and Pitx2 cooperate in stimulation of FSHβ gene transcription

Cited by 21 publications

References 46 publications

Minireview: Activin Signaling in Gonadotropes: What Does the FOX say… to the SMAD?

Minireview: Activin Signaling in Gonadotropes: What Does the FOX say… to the SMAD?

Mechanisms of FSH synthesis: what we know, what we don't, and why you should care

Emerging Biomarkers in Breast Cancer Care

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