Tracking the Activation of Stat5 through the Expression of an Inducible Reporter Gene in a Transgenic Mouse Line

Bednorz, Nadja Lydia; Brill, Boris; Klein, Andreas; Gäbel, Katrin; Groner, Bernd

doi:10.1210/en.2011-0053

Cited by 9 publications

(6 citation statements)

References 55 publications

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“…STAT3 mRNA levels are high in the mammary epithelium of adult virgins and remain elevated till pregnancy day 5, when they begin to drop and, concomitantly, STAT5 levels begin to rise (Philp et al, 1996). STAT5 activation, however, does not occur maximally until mid to late pregnancy (Bednorz et al, 2011). Interestingly, Shp2, a phosphatase known to inhibit STAT activation, appears to stabilize STAT5 activation in the pregnant/lactating mammary gland while simultaneously preventing the activation of STAT3 (Ke et al, 2006).…”

Section: Mammary Gland Differentiationmentioning

confidence: 99%

STAT signaling in mammary gland differentiation, cell survival and tumorigenesis

Haricharan

2014

Molecular and Cellular Endocrinology

103

111

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The mammary gland is a unique organ that undergoes extensive and profound changes during puberty, menstruation, pregnancy, lactation and involution. The changes that take place during puberty involve large-scale proliferation and invasion of the fat-pad. During pregnancy and lactation, the mammary cells are exposed to signaling pathways that inhibit apoptosis, induce proliferation and invoke terminal differentiation. Finally, during involution the mammary gland is exposed to milk stasis, programed cell death and stromal reorganization to clear the differentiated milk-producing cells. Not surprisingly, the signaling pathways responsible for bringing about these changes in breast cells are often subverted during the process of tumorigenesis. The STAT family of proteins is involved in every stage of mammary gland development, and is also frequently implicated in breast tumorigenesis. While the roles of STAT3 and STAT5 during mammary gland development and tumorigenesis are well studied, others members, e.g. STAT1 and STAT6, have only recently been observed to play a role in mammary gland biology. Continued investigation into the STAT protein network in the mammary gland will likely yield new biomarkers and risk factors for breast cancer, and may also lead to novel prophylactic or therapeutic strategies against breast cancer.

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Section: Mammary Gland Differentiationmentioning

confidence: 99%

STAT signaling in mammary gland differentiation, cell survival and tumorigenesis

Haricharan

2014

Molecular and Cellular Endocrinology

103

111

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“…16 pStat5 is essential in the mammary gland during the prior stages of pregnancy and progressively declines during lactation and early involution. 38,43 pStat5 is activated by upstream Neuregulin/ErbB signaling. 44,45 In agreement, at involution day 1 neuregulin 1 and 2 (NRG1 and NRG2) genes are repressed in p63 þ / À glands, but no longer at day 3 when their expression has declined even in WT glands (Figure 3d).…”

mentioning

confidence: 99%

p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis

et al. 2014

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In embryogenesis, p63 is essential to develop mammary glands. In the adult mammary gland, p63 is highly expressed in the basal cell layer that comprises myoepithelial and interspersed stem/progenitor cells, and has limited expression in luminal epithelial cells. In adult skin, p63 has a crucial role in the maintenance of epithelial stem cells. However, it is unclear whether p63 also has an equivalent role as a stem/progenitor cell factor in adult mammary epithelium. We show that p63 is essential in vivo for the survival and maintenance of parity-identified mammary epithelial cells (PI-MECs), a pregnancy-induced heterogeneous population that survives post-lactational involution and contain multipotent progenitors that give rise to alveoli and ducts in subsequent pregnancies. p63 þ / À glands are normal in virgin, pregnant and lactating states. Importantly, however, during the apoptotic phase of post-lactational involution p63 þ / À glands show a threefold increase in epithelial cell death, concomitant with increased activation of the oncostatin M/Stat3 and p53 pro-apoptotic pathways, which are responsible for this phase. Thus, p63 is a physiologic antagonist of these pathways specifically in this regressive stage. After the restructuring phase when involution is complete, mammary glands of p63 þ / À mice again exhibit normal epithelial architecture by conventional histology. However, using Rosa LSL-LacZ ;WAP-Cre transgenics (LSL-LacZ, lox-stop-lox b-galactosidase), a genetic in vivo labeling system for PI-MECs, we find that p63 þ / À glands have a 30% reduction in the number of PI-MEC progenitors and their derivatives. Importantly, PI-MECs are also cellular targets of pregnancy-promoted ErbB2 tumorigenesis. Consistent with their PI-MEC pool reduction, one-time pregnant p63 þ / À ErbB2 mice are partially protected from breast tumorigenesis, exhibiting extended tumor-free and overall survival, and reduced tumor multiplicity compared with their p63 þ / þ ErbB2 littermates. Conversely, in virgin ErbB2 mice p63 heterozygosity provides no survival advantage. In sum, our data establish that p63 is an important survival factor for pregnancy-identified PI-MEC progenitors in breast tissue in vivo.

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“…These genes are present in the JAK/STAT pathway, which is the main signaling route for many cytokines [73]. In particular, STAT5 has been shown to have important functions in reproduction and also in NR3C1-mediated transcriptional action [74,75], via active NR3C1-mediated transcription and T-cell differentiation [76]. Natural mating downregulated STAT5A in almost all tissues (ProxUt, DistUt, and Isth; q < 0.05) while STAT5B was only modified in the proximal uterus, and only by the sperm treatments (mating and semen-AI).…”

Section: Discussionmentioning

confidence: 99%

Natural Mating Differentially Triggers Expression of Glucocorticoid Receptor (NR3C1)-Related Genes in the Preovulatory Porcine Female Reproductive Tract

Ruiz-Conca

Gardela

Martínez

et al. 2020

IJMS

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Mating initiates dynamic modifications of gene transcription in the female reproductive tract, preparing the female for fertilization and pregnancy. Glucocorticoid signaling is essential for the homeostasis of mammalian physiological functions. This complex glucocorticoid regulation is mediated through the glucocorticoid receptor, also known as nuclear receptor subfamily 3 group C member 1 (NR3C1/GR) and related genes, like 11β-hydroxysteroid dehydrogenases (HSD11Bs) and the FK506-binding immunophilins, FKBP5 and FKBP4. This study tested the transcriptome changes in NR3C1/GR regulation in response to natural mating and/or cervical deposition of the sperm-peak ejaculate fraction collected using the gloved-hand method (semen or only its seminal plasma), in the preovulatory pig reproductive tract (cervix to infundibulum, 24 h after mating/insemination/infusion treatments). Porcine cDNA microarrays revealed 22 NR3C1-related transcripts, and changes in gene expression were triggered by all treatments, with natural mating showing the largest differences, including NR3C1, FKBP5, FKBP4, hydroxysteroid 11-beta dehydrogenase 1 and 2 (HSD11B1, HSD11B2), and the signal transducer and activator of transcription 5A (STAT5A). Our data suggest that natural mating induces expression changes that might promote a reduction of the cortisol action in the oviductal sperm reservoir. Together with the STAT-mediated downregulation of cytokine immune actions, this reduction may prevent harmful effects by promoting tolerance towards the spermatozoa stored in the oviduct and perhaps elicit spermatozoa activation and detachment after ovulation.

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Tracking the Activation of Stat5 through the Expression of an Inducible Reporter Gene in a Transgenic Mouse Line

Cited by 9 publications

References 55 publications

STAT signaling in mammary gland differentiation, cell survival and tumorigenesis

STAT signaling in mammary gland differentiation, cell survival and tumorigenesis

p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis

Natural Mating Differentially Triggers Expression of Glucocorticoid Receptor (NR3C1)-Related Genes in the Preovulatory Porcine Female Reproductive Tract

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