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Key stages in mammary gland development. Secretory activation in the mammary gland: it's not just about milk protein synthesis!

Anderson SM, Rudolph MC, McManaman JL, Neville MC - Breast Cancer Res. (2007)

Bottom Line: Much of the research to date on mammary epithelial differentiation has focused upon expression of milk protein genes, providing a somewhat distorted view of alveolar differentiation and secretory activation.While expression of milk protein genes increases during pregnancy and at secretory activation, the genes whose expression is more tightly regulated at this transition are those that regulate lipid biosynthesis.The sterol regulatory element binding protein (SREBP) family of transcription factors is recognized as regulating fatty acid and cholesterol biosynthesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, University of Colorado Health Sciences Center, East 17th Avenue, Aurora, CO 80045, USA. Steve.Anderson@uchsc.edu

ABSTRACT
The transition from pregnancy to lactation is a critical event in the survival of the newborn since all the nutrient requirements of the infant are provided by milk. While milk contains numerous components, including proteins, that aid in maintaining the health of the infant, lactose and milk fat represent the critical energy providing elements of milk. Much of the research to date on mammary epithelial differentiation has focused upon expression of milk protein genes, providing a somewhat distorted view of alveolar differentiation and secretory activation. While expression of milk protein genes increases during pregnancy and at secretory activation, the genes whose expression is more tightly regulated at this transition are those that regulate lipid biosynthesis. The sterol regulatory element binding protein (SREBP) family of transcription factors is recognized as regulating fatty acid and cholesterol biosynthesis. We propose that SREBP1 is a critical regulator of secretory activation with regard to lipid biosynthesis, in a manner that responds to diet, and that the serine/threonine protein kinase Akt influences this process, resulting in a highly efficient lipid synthetic organ that is able to support the nutritional needs of the newborn.

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Model predicting critical regulators of secretory activation in the mammary gland. The transcription of milk protein genes is induced by the binding of prolactin to its receptor (the PRLR) and regulated by the STAT5 and ELF5 transcription factors. Translation of milk protein genes may be enhanced by Akt1 acting on their substrates, such as glycogen synthase kinse (GSK)-3/eIF2B, mammalian target of rapamycin (mTOR)/S6 kinase and mTOR/4E-BP1. Transcription of glucose transporter (GLUT)1 may be induced by the PRLR and Akt1 may contribute to either the expression or localization of GLUT1. The response of the mammary gland to dietary fat is sensed by sterol regulatory element binding protein (SREBP), and the stability of SREBP may be enhanced by Akt1-mediated inhibition of GSK3, since phosphorylation of SREBP by GSK3 enhances the ubiquitination and degradation of SREBP in the nucleus.
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Figure 8: Model predicting critical regulators of secretory activation in the mammary gland. The transcription of milk protein genes is induced by the binding of prolactin to its receptor (the PRLR) and regulated by the STAT5 and ELF5 transcription factors. Translation of milk protein genes may be enhanced by Akt1 acting on their substrates, such as glycogen synthase kinse (GSK)-3/eIF2B, mammalian target of rapamycin (mTOR)/S6 kinase and mTOR/4E-BP1. Transcription of glucose transporter (GLUT)1 may be induced by the PRLR and Akt1 may contribute to either the expression or localization of GLUT1. The response of the mammary gland to dietary fat is sensed by sterol regulatory element binding protein (SREBP), and the stability of SREBP may be enhanced by Akt1-mediated inhibition of GSK3, since phosphorylation of SREBP by GSK3 enhances the ubiquitination and degradation of SREBP in the nucleus.

Mentions: A mechanism by which Akt might regulate activation of SREBPs has been suggested by the recent work of Sundqvist and colleagues [101], who demonstrated that degradation of SREBP is regulated by phosphorylation of Thr426 and Ser430. These phosphorylation sites serve as recognition motifs for the binding of the SCFFbw7 ubiquitin ligase. Binding of SCFFbw7 to SREBP enhances the ubiquitination and degradation of SREBP [101]; thus, phosphorylation of SREBP results in the negative regulation of SREBP transcriptional activity, and the downregulation of SREBP-dependent genes. Phosphorylation of Thr426 and Ser430 is mediated by glycogen synthase kinse (GSK)-3 [101]; the link to Akt is provided by the fact that GSK-3 is the first known substrate of Akt, and phosphorylation of it by Akt inhibits its catalytic activity [102]. Therefore, expression of activated Akt in cells should inhibit the catalytic activity of GSK-3, leading to a decrease in the phosphorylation of SREBP by it and a decrease in the resulting degradation of SREBP; all of these changes should result in the increased transcription of SREBP-dependent genes, as has been observed in vitro [100]. Our model proposes that Akt plays a similar function in the in vivo mammary gland, acting as a major regulator of fatty acid synthesis at the onset of lactation by stabilizing SREBPs (Figure 8).


Key stages in mammary gland development. Secretory activation in the mammary gland: it's not just about milk protein synthesis!

Anderson SM, Rudolph MC, McManaman JL, Neville MC - Breast Cancer Res. (2007)

Model predicting critical regulators of secretory activation in the mammary gland. The transcription of milk protein genes is induced by the binding of prolactin to its receptor (the PRLR) and regulated by the STAT5 and ELF5 transcription factors. Translation of milk protein genes may be enhanced by Akt1 acting on their substrates, such as glycogen synthase kinse (GSK)-3/eIF2B, mammalian target of rapamycin (mTOR)/S6 kinase and mTOR/4E-BP1. Transcription of glucose transporter (GLUT)1 may be induced by the PRLR and Akt1 may contribute to either the expression or localization of GLUT1. The response of the mammary gland to dietary fat is sensed by sterol regulatory element binding protein (SREBP), and the stability of SREBP may be enhanced by Akt1-mediated inhibition of GSK3, since phosphorylation of SREBP by GSK3 enhances the ubiquitination and degradation of SREBP in the nucleus.
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Related In: Results  -  Collection

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Figure 8: Model predicting critical regulators of secretory activation in the mammary gland. The transcription of milk protein genes is induced by the binding of prolactin to its receptor (the PRLR) and regulated by the STAT5 and ELF5 transcription factors. Translation of milk protein genes may be enhanced by Akt1 acting on their substrates, such as glycogen synthase kinse (GSK)-3/eIF2B, mammalian target of rapamycin (mTOR)/S6 kinase and mTOR/4E-BP1. Transcription of glucose transporter (GLUT)1 may be induced by the PRLR and Akt1 may contribute to either the expression or localization of GLUT1. The response of the mammary gland to dietary fat is sensed by sterol regulatory element binding protein (SREBP), and the stability of SREBP may be enhanced by Akt1-mediated inhibition of GSK3, since phosphorylation of SREBP by GSK3 enhances the ubiquitination and degradation of SREBP in the nucleus.
Mentions: A mechanism by which Akt might regulate activation of SREBPs has been suggested by the recent work of Sundqvist and colleagues [101], who demonstrated that degradation of SREBP is regulated by phosphorylation of Thr426 and Ser430. These phosphorylation sites serve as recognition motifs for the binding of the SCFFbw7 ubiquitin ligase. Binding of SCFFbw7 to SREBP enhances the ubiquitination and degradation of SREBP [101]; thus, phosphorylation of SREBP results in the negative regulation of SREBP transcriptional activity, and the downregulation of SREBP-dependent genes. Phosphorylation of Thr426 and Ser430 is mediated by glycogen synthase kinse (GSK)-3 [101]; the link to Akt is provided by the fact that GSK-3 is the first known substrate of Akt, and phosphorylation of it by Akt inhibits its catalytic activity [102]. Therefore, expression of activated Akt in cells should inhibit the catalytic activity of GSK-3, leading to a decrease in the phosphorylation of SREBP by it and a decrease in the resulting degradation of SREBP; all of these changes should result in the increased transcription of SREBP-dependent genes, as has been observed in vitro [100]. Our model proposes that Akt plays a similar function in the in vivo mammary gland, acting as a major regulator of fatty acid synthesis at the onset of lactation by stabilizing SREBPs (Figure 8).

Bottom Line: Much of the research to date on mammary epithelial differentiation has focused upon expression of milk protein genes, providing a somewhat distorted view of alveolar differentiation and secretory activation.While expression of milk protein genes increases during pregnancy and at secretory activation, the genes whose expression is more tightly regulated at this transition are those that regulate lipid biosynthesis.The sterol regulatory element binding protein (SREBP) family of transcription factors is recognized as regulating fatty acid and cholesterol biosynthesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, University of Colorado Health Sciences Center, East 17th Avenue, Aurora, CO 80045, USA. Steve.Anderson@uchsc.edu

ABSTRACT
The transition from pregnancy to lactation is a critical event in the survival of the newborn since all the nutrient requirements of the infant are provided by milk. While milk contains numerous components, including proteins, that aid in maintaining the health of the infant, lactose and milk fat represent the critical energy providing elements of milk. Much of the research to date on mammary epithelial differentiation has focused upon expression of milk protein genes, providing a somewhat distorted view of alveolar differentiation and secretory activation. While expression of milk protein genes increases during pregnancy and at secretory activation, the genes whose expression is more tightly regulated at this transition are those that regulate lipid biosynthesis. The sterol regulatory element binding protein (SREBP) family of transcription factors is recognized as regulating fatty acid and cholesterol biosynthesis. We propose that SREBP1 is a critical regulator of secretory activation with regard to lipid biosynthesis, in a manner that responds to diet, and that the serine/threonine protein kinase Akt influences this process, resulting in a highly efficient lipid synthetic organ that is able to support the nutritional needs of the newborn.

Show MeSH