Regulation of the JAK2-STAT5 Pathway by Signaling Molecules in the Mammary Gland

Tian, Min; Qi, Yingao; Zhang, Xiaoli; Wu, Zhihui; Chen, Jiaming; Chen, Fang; Guan, Wutai; Zhang, Shihai

doi:10.3389/fcell.2020.604896

Cited by 34 publications

(23 citation statements)

References 113 publications

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“…In order to nominate key genes and factors that might be responsible for pathway-level changes in these two subclusters, we looked at the expression of key regulators that were differentially expressed with time postpartum, including those important for hormone signaling, growth factor signaling, AP-1 signaling, factors involved in STAT5 signaling, and several milk production component genes ( Fig. 5 C ) ( 55 – 57 ). We found that the expression of several hormone receptor genes changed in opposite directions with time in the LC1 and secretory lactocyte subclusters, with estrogen receptor ( ESR1 ) and prolactin receptor ( PRLR ) increased in secretory lactocytes and decreased in LC1 cells.…”

Section: Resultsmentioning

confidence: 99%

Cellular and transcriptional diversity over the course of human lactation

Nyquist

Gao

Haining

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance Human breast milk is the nutritional food source evolved specifically to meet the needs of infants, but much remains to be learned about its composition and changes over the course of lactation. Our description of the cellular components of breast milk, their associations with maternal–infant dyad metadata, and quantification of alterations at the gene and pathway levels provide a longitudinal picture of human breast milk cells across lactational time. These results pave the way for improved therapeutic support of healthy lactation and milk production.

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Section: Resultsmentioning

confidence: 99%

Cellular and transcriptional diversity over the course of human lactation

Nyquist

Gao

Haining

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Prolactin is a key hormone regulating milk protein synthesis in mammals [49]. In bovine mammary epithelial cells, prolactin activates STAT5 phosphorylation via the prolactin receptor, promotes the expression of β-casein gene and maintains cell proliferation and milk protein synthesis [50,51].…”

Section: Discussionmentioning

confidence: 99%

Mutation of Signal Transducer and Activator of Transcription 5 (STAT5) Binding Sites Decreases Milk Allergen αS1-Casein Content in Goat Mammary Epithelial Cells

Song

Luo

Huang

et al. 2022

Foods

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αS1-Casein (encoded by the CSN1S1 gene) is associated with food allergy more than other milk protein components. Milk allergy caused by αS1-casein is derived from cow milk, goat milk and other ruminant milk. However, little is known about the transcription regulation of αS1-casein synthesis in dairy goats. This study aimed to investigate the regulatory roles of signal transducer and activator of transcription 5 (STAT5) on αS1-casein in goat mammary epithelial cells (GMEC). Deletion analysis showed that the core promoter region of CSN1S1 was located at −110 to −18 bp upstream of transcription start site, which contained two putative STAT5 binding sites (gamma-interferon activation site, GAS). Overexpression of STAT5a gene upregulated the mRNA level and the promoter activity of the CSN1S1 gene, and STAT5 inhibitor decreased phosphorylated STAT5 in the nucleus and CSN1S1 transcription activity. Further, GAS site-directed mutagenesis and chromatin immunoprecipitation (ChIP) assays revealed that GAS1 and GAS2 sites in the CSN1S1 promoter core region were binding sites of STAT5. Taken together, STAT5 directly regulates CSN1S1 transcription by GAS1 and GAS2 sites in GMEC, and the mutation of STAT5 binding sites could downregulate CSN1S1 expression and decrease αS1-casein synthesis, which provide the novel strategy for reducing the allergic potential of goat milk and improving milk quality in ruminants.

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“…STAT5A is a core lactational gene that is involved in proliferation, cell survival, and milk component synthesis. 70,80,[82][83][84][85][86] Interestingly, we observe decreases in STAT5a/b expression and downstream targets such as AKT1 72 , ACACA (a gene involved in fatty acid synthesis), and CSN2 (the gene encoding beta-casein) over the course of lactation.…”

Section: Discussionmentioning

confidence: 99%

“…In order to nominate key genes and factors that might be responsible for pathwaylevel changes in these two sub-clusters, we looked at the expression of key regulators that were differentially expressed with time postpartum, including those important for hormone signaling, growth factor signaling, AP-1 signaling, factors involved in STAT5 signaling, and several milk production component genes (Figure 5D) [70][71][72] . We found that the expression of several hormone receptor genes changed in opposite directions with time in the LALBA low epithelial and secretory lactocyte sub-clusters, where estrogen receptor (ESR1) and prolactin receptor (PRLR) increased in secretory lactocytes and decreased in LALBA low epithelial cells.…”

Section: Ementioning

confidence: 99%

Cellular and transcriptional diversity over the course of human lactation

Nyquist

Gao

Haining

et al. 2021

Preprint

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Human breast milk is a dynamic fluid that contains millions of cells, but their identities and phenotypic properties are poorly understood. We used single-cell RNA-seq (scRNA-seq) to characterize the transcriptomes of cells from human breast milk (hBM) across lactational time from 3 to 632 days postpartum in 15 donors. We find that the majority of cells in human breast milk are lactocytes, a specialized epithelial subset, and cell type frequencies shift over the course of lactation yielding greater epithelial diversity at later points. Analysis of lactocytes reveals a continuum of cell states characterized by transcriptional changes in hormone, growth factor, and milk production related pathways. Generalized additive models suggest that one sub-cluster, LALBAlow epithelial cells, increase as a function of time postpartum, daycare attendance, and the use of hormonal birth control. We identify several sub-clusters of macrophages in hBM that are enriched for tolerogenic functions, possibly playing a role in protecting the mammary gland during lactation. Our description of the cellular components of breast milk, their association with maternal-infant dyad metadata and quantification of alterations at the gene and pathways levels provides the first detailed longitudinal picture of human breast milk cells across lactational time. This work paves the way for future investigations of how a potential division of cellular labor and differential hormone regulation might be leveraged therapeutically to support healthy lactation and potentially aid in milk production.

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Regulation of the JAK2-STAT5 Pathway by Signaling Molecules in the Mammary Gland

Cited by 34 publications

References 113 publications

Cellular and transcriptional diversity over the course of human lactation

Cellular and transcriptional diversity over the course of human lactation

Mutation of Signal Transducer and Activator of Transcription 5 (STAT5) Binding Sites Decreases Milk Allergen αS1-Casein Content in Goat Mammary Epithelial Cells

Cellular and transcriptional diversity over the course of human lactation

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