Limits...
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.

Show MeSH
Expression patterns of milk protein genes. The main graph shows genes whose expression increases more than two-fold at parturition. The inset shows genes with casein-like expression patterns whose mRNA increases mainly during pregnancy. All data are normalized to the level of expression at day 17 of pregnancy (P17). ADPH, adipophilin; MFGM, milk fat globule-EGF-factor; PTHrP, parathyroid hormone related protein; WAP, whey acidic protein; WDNM1, Westmeade DMBA8 nonmetastatic cDNA1; xanthine DH, xanthine oxidoreductase.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC1851396&req=5

Figure 4: Expression patterns of milk protein genes. The main graph shows genes whose expression increases more than two-fold at parturition. The inset shows genes with casein-like expression patterns whose mRNA increases mainly during pregnancy. All data are normalized to the level of expression at day 17 of pregnancy (P17). ADPH, adipophilin; MFGM, milk fat globule-EGF-factor; PTHrP, parathyroid hormone related protein; WAP, whey acidic protein; WDNM1, Westmeade DMBA8 nonmetastatic cDNA1; xanthine DH, xanthine oxidoreductase.

Mentions: Figure 4 shows a summary of array data obtained in both the Neville laboratory [33] and the Gusterson laboratory [55], with expression levels of the 14 major milk proteins plotted as a ratio to their expression on day 17 of pregnancy. Changes in mRNA expression fall into two categories: The first group of proteins is shown in the inset in Figure 4; and the mRNA expression of this group increases 3- to 50-fold during pregnancy. This category includes most of the caseins, Westmeade DMBA8 nonmetastatic cDNA1 (WDNM1), milk fat globule-EGF-factor-8 (MFGM-E8), WAP and adipophilin. Expression of the mRNA for these proteins is upregulated no more than two-fold at secretory activation. Most of the caseins are expressed in early pregnancy at 30% of the level on day 17 of pregnancy; on the other hand, the expression levels of WAP and WDNM1 mRNAs appear to be insignificant in early pregnancy, turning on between P7 and P12. Despite these differences, expression of most of these proteins has been shown to be regulated by PRL [37] acting through phosphorylation of STAT-5 [56-59]. During pregnancy in the rodent, when PRL levels are known to be low, it is likely that differentiated expression levels respond to placental lactogens [37]. The levels of PRL rise late in pregnancy; however, as noted above, the effect of PRL is suppressed by the high serum levels of progesterone [37-40]. This being the case, synthesis of these proteins, as opposed to transcription of their genes, must be regulated at a level upstream of mRNA transcription. Indeed, in very elegant work in the laboratories of Rhoads and Barash [60,61], both polyadenylation of β-casein mRNA and amino acid availability appear to be involved in the translational regulation of milk protein synthesis. It is tempting to speculate that, since the expression of Akt1 increases at secretory activation, Akt could stimulate translation of milk proteins through its ability to phosphorylate 4E-BP1, a negative regulator of translation [62]; however, no evidence exists to support this speculation. Likewise the Akt-dependent activation of mammalian target of rapamycin (mTOR) could stimulate translation through S6 kinase and eEF2 [63,64].


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)

Expression patterns of milk protein genes. The main graph shows genes whose expression increases more than two-fold at parturition. The inset shows genes with casein-like expression patterns whose mRNA increases mainly during pregnancy. All data are normalized to the level of expression at day 17 of pregnancy (P17). ADPH, adipophilin; MFGM, milk fat globule-EGF-factor; PTHrP, parathyroid hormone related protein; WAP, whey acidic protein; WDNM1, Westmeade DMBA8 nonmetastatic cDNA1; xanthine DH, xanthine oxidoreductase.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1851396&req=5

Figure 4: Expression patterns of milk protein genes. The main graph shows genes whose expression increases more than two-fold at parturition. The inset shows genes with casein-like expression patterns whose mRNA increases mainly during pregnancy. All data are normalized to the level of expression at day 17 of pregnancy (P17). ADPH, adipophilin; MFGM, milk fat globule-EGF-factor; PTHrP, parathyroid hormone related protein; WAP, whey acidic protein; WDNM1, Westmeade DMBA8 nonmetastatic cDNA1; xanthine DH, xanthine oxidoreductase.
Mentions: Figure 4 shows a summary of array data obtained in both the Neville laboratory [33] and the Gusterson laboratory [55], with expression levels of the 14 major milk proteins plotted as a ratio to their expression on day 17 of pregnancy. Changes in mRNA expression fall into two categories: The first group of proteins is shown in the inset in Figure 4; and the mRNA expression of this group increases 3- to 50-fold during pregnancy. This category includes most of the caseins, Westmeade DMBA8 nonmetastatic cDNA1 (WDNM1), milk fat globule-EGF-factor-8 (MFGM-E8), WAP and adipophilin. Expression of the mRNA for these proteins is upregulated no more than two-fold at secretory activation. Most of the caseins are expressed in early pregnancy at 30% of the level on day 17 of pregnancy; on the other hand, the expression levels of WAP and WDNM1 mRNAs appear to be insignificant in early pregnancy, turning on between P7 and P12. Despite these differences, expression of most of these proteins has been shown to be regulated by PRL [37] acting through phosphorylation of STAT-5 [56-59]. During pregnancy in the rodent, when PRL levels are known to be low, it is likely that differentiated expression levels respond to placental lactogens [37]. The levels of PRL rise late in pregnancy; however, as noted above, the effect of PRL is suppressed by the high serum levels of progesterone [37-40]. This being the case, synthesis of these proteins, as opposed to transcription of their genes, must be regulated at a level upstream of mRNA transcription. Indeed, in very elegant work in the laboratories of Rhoads and Barash [60,61], both polyadenylation of β-casein mRNA and amino acid availability appear to be involved in the translational regulation of milk protein synthesis. It is tempting to speculate that, since the expression of Akt1 increases at secretory activation, Akt could stimulate translation of milk proteins through its ability to phosphorylate 4E-BP1, a negative regulator of translation [62]; however, no evidence exists to support this speculation. Likewise the Akt-dependent activation of mammalian target of rapamycin (mTOR) could stimulate translation through S6 kinase and eEF2 [63,64].

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