Socs 3 modulates the activity of the transcription factor Stat3 in mammary tissue and controls alveolar homeostasis

Robinson, Gertraud W.; Pacher‐Zavisin, Margit; Zhu, Bing; Yoshimura, Akihiko; Hennighausen, Lothar

doi:10.1002/dvdy.21058

Cited by 20 publications

(15 citation statements)

References 30 publications

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“…26 These observations indicate that Socs3 is not a key regulator of PRL signal transduction and Stat5 activity in vivo. Our findings contrast with those recently reported by Robinson et al 54 in which ablation of Socs3 using MMTV-Cre (strain A) transgenic mice led to impaired lactation, although this was not associated with a reduction in the expression of milk proteins or differentiation markers. However, alveolar cells in the Socs3-deficient glands appeared more condensed in morphology, perhaps reflecting elevated epithelial apoptosis as Stat3 activation was elevated at day 1 of lactation.…”

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confidence: 99%

“…However, alveolar cells in the Socs3-deficient glands appeared more condensed in morphology, perhaps reflecting elevated epithelial apoptosis as Stat3 activation was elevated at day 1 of lactation. 54 Taken together, these data strongly suggest that Socs3 is not a downstream target of Stat5 and emphasize the inconclusive nature of in vitro overexpression studies when addressing the biological significance of SOCS proteins. The phenotypic differences observed by us and Robinson et al 54 probably reflect the efficiency and timing of excision of the conditional Socs3 allele.…”

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 83%

“…54 Taken together, these data strongly suggest that Socs3 is not a downstream target of Stat5 and emphasize the inconclusive nature of in vitro overexpression studies when addressing the biological significance of SOCS proteins. The phenotypic differences observed by us and Robinson et al 54 probably reflect the efficiency and timing of excision of the conditional Socs3 allele. In any event, both studies highlight the importance of the kinetics of Stat activation (reciprocal phosphorylation) in the mammary epithelium and the critical role of Stat proteins in controlling the switch from lactation to involution.…”

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 83%

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Knocking Off SOCS Genes in the Mammary Gland

Sutherland¹,

Lindeman²,

Visvader³

2007

Cell Cycle

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confidence: 99%

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 83%

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 83%

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Knocking Off SOCS Genes in the Mammary Gland

Sutherland¹,

Lindeman²,

Visvader³

2007

Cell Cycle

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“…This gene, important for the mammary tissue homeostasis [50,51], encodes an intracellular inhibitor of cytokine signaling that acts in a classical negative feedback loop [52,53]. This is consistent with the fact that the up-regulation of different cytokine encoding genes such as IL-1β , TNFα and CCL4 by MEC is restricted at the very early stages of infection, before a decrease at 30 hpi.…”

Section: Discussionsupporting

confidence: 58%

Contribution of mammary epithelial cells to the immune response during early stages of a bacterial infection to Staphylococcus aureus

Brenaut

Lefèvre

Rau

et al. 2014

Vet Res

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To differentiate between the contribution of mammary epithelial cells (MEC) and infiltrating immune cells to gene expression profiles of mammary tissue during early stage mastitis, we investigated in goats the in vivo transcriptional response of MEC to an experimental intra mammary infection (IMI) with Staphylococcus aureus, using a non-invasive RNA sampling method from milk fat globules (MFG). Microarrays were used to record gene expression patterns during the first 24 hours post-infection (hpi). This approach was combined with laser capture microdissection of MEC from frozen slides of mammary tissue to analyze some relevant genes at 30 hpi. During the early stages post-inoculation, MEC play an important role in the recruitment and activation of inflammatory cells through the IL-8 signalling pathway and initiate a sharp induction of innate immune genes predominantly associated with the pro-inflammatory response. At 30 hpi, MEC express genes encoding different acute phase proteins, including SAA3, SERPINA1 and PTX3 and factors, such as S100A12, that contribute directly to fighting the infection. No significant change in the expression of genes encoding caseins was observed until 24 hpi, thus validating our experimental model to study early stages of infection before the occurrence of tissue damage, since the milk synthesis function is still operative. This is to our knowledge the first report showing in vivo, in goats, how MEC orchestrate the innate immune response to an IMI challenge with S. aureus. Moreover, the non-invasive sampling method of mammary representative RNA from MFG provides a valuable tool to easily follow the dynamics of gene expression in MEC to search for sensitive biomarkers in milk for early detection of mastitis and therefore, to successfully improve the treatment and thus animal welfare.

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“…However, the interaction of these STAT signaling pathways at the onset of involution is unclear, although it may be mediated by suppressor of cytokine signaling 3 (SOCS3). Activated STAT3 upregulates SOCS3 (Alexander and Hilton, 2004;Clarkson et al, 2006), which then regulates further STAT3 activation to ensure controlled apoptosis of MEC and mammary tissue remodeling during involution Robinson et al, 2007). In vitro studies show that SOCS3 can inhibit PRL induction of milk protein gene expression and STAT5 activation, through direct interaction with PRL receptors (PRLR; Dif et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Cell survival signaling in the bovine mammary gland during the transition from lactation to involution

Singh

Vetharaniam

Dobson

et al. 2016

Journal of Dairy Science

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In dairy cows, mammary gland involution, and thus a decline in milk production, occurs following peak lactation. To examine the cell signaling pathways regulating involution of the mammary gland, signal transducer and activator of transcription factors (STAT5 and 3), suppressors of cytokine signaling (SOCS1-3 and CIS), insulin-like growth factors (IGF1 and 2), and protein kinase B (Akt) were examined. Mammary involution was induced by termination of milking, and alveolar tissue was collected from 52 nonpregnant, primiparous, mid-lactation Holstein-Friesian cows killed at 0, 6, 12, 18, 24, 36, 72, and 192h postmilking. Qualitative immunohistochemistry showed that activated (phosphorylated) STAT5-P was localized in nuclei of mammary epithelial cells at the early time points, with detection levels decreasing by 24h postmilking. In contrast, STAT3-P was barely detectable at the early time points, with detection levels increasing following longer postmilking periods. This was supported by Western analysis, which showed a decline in STAT5 and STAT5-P protein levels by 24h postmilking, no change in STAT3 levels, and an increase in STAT3-P protein (barely detectable at the early time points) by 72h postmilking. Quantitative real-time reverse transcription PCR analysis showed SOCS1 and SOCS3 mRNA increased by 72h postmilking compared with 6h postmilking. The SOCS2 mRNA remained unchanged across the time series, whereas CIS decreased by 18h postmilking and remained lower compared with that at 6h postmilking until 72h postmilking. The IGF1 mRNA increased by 192h postmilking, whereas IGF2 mRNA decreased by 18h postmilking compared with 6h postmilking. The IGFBP5 mRNA and protein levels of Akt and Akt-P remained unchanged over the time series. These results show that reciprocal activation of STAT5 and STAT3 occurs at the onset of mammary gland involution in the bovine, albeit at a slower rate than in rodents. Mathematical modeling of the pathways indicated that activated STAT3 could block the STAT5 pathway by upregulating SOCS3. The regulation of IGF1-Akt signaling suggests that by 192h postmilking in dairy cows, the involution process is still in the reversible phase, with quiescent mammary epithelial cells not yet in the senescent phase.

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Socs 3 modulates the activity of the transcription factor Stat3 in mammary tissue and controls alveolar homeostasis

Cited by 20 publications

References 30 publications

Knocking Off SOCS Genes in the Mammary Gland

Knocking Off SOCS Genes in the Mammary Gland

Contribution of mammary epithelial cells to the immune response during early stages of a bacterial infection to Staphylococcus aureus

Cell survival signaling in the bovine mammary gland during the transition from lactation to involution

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