Document Detail


Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways.
MedLine Citation:
PMID:  23028142     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Extrapituitary prolactin (Prl) is produced in humans and rodents; however, little is known about its in vivo regulation or physiological function. We now report that autocrine prolactin is required for terminal mammary epithelial differentiation during pregnancy and that its production is regulated by the Pten-PI3K-Akt pathway. Conditional activation of the PI3K-Akt pathway in the mammary glands of virgin mice by either Akt1 expression or Pten deletion rapidly induced terminal mammary epithelial differentiation accompanied by the synthesis of milk despite the absence of lobuloalveolar development. Surprisingly, we found that mammary differentiation was due to the PI3K-Akt-dependent synthesis and secretion of autocrine prolactin and downstream activation of the prolactin receptor (Prlr)-Jak-Stat5 pathway. Consistent with this, Akt-induced mammary differentiation was abrogated in Prl(-/-), Prlr(-/-), and Stat5(-/-) mice. Furthermore, cells treated with conditioned medium from mammary glands in which Akt had been activated underwent rapid Stat5 phosphorylation in a manner that was blocked by inhibition of Jak2, treatment with an anti-Prl antibody, or deletion of the prolactin gene. Demonstrating a physiological requirement for autocrine prolactin, mammary glands from lactation-defective Akt1(-/-);Akt2(+/-) mice failed to express autocrine prolactin or activate Stat5 during late pregnancy despite normal levels of circulating serum prolactin and pituitary prolactin production. Our findings reveal that PI3K-Akt pathway activation is necessary and sufficient to induce autocrine prolactin production in the mammary gland, Stat5 activation, and terminal mammary epithelial differentiation, even in the absence of the normal developmental program that prepares the mammary gland for lactation. Together, these findings identify a function for autocrine prolactin during normal development and demonstrate its endogenous regulation by the PI3K-Akt pathway.
Authors:
Chien-Chung Chen; Douglas B Stairs; Robert B Boxer; George K Belka; Nelson D Horseman; James V Alvarez; Lewis A Chodosh
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Genes & development     Volume:  26     ISSN:  1549-5477     ISO Abbreviation:  Genes Dev.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-02     Completed Date:  2012-12-05     Revised Date:  2014-01-07    
Medline Journal Info:
Nlm Unique ID:  8711660     Medline TA:  Genes Dev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2154-68     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Autocrine Communication / physiology
Cell Differentiation
Cells, Cultured
Down-Regulation
Female
Gene Deletion
Gene Expression Regulation*
Lactation / genetics,  physiology*
Mammary Glands, Animal / cytology,  metabolism
Mice
Milk Proteins / metabolism
PTEN Phosphohydrolase / genetics
Pregnancy
Prolactin / genetics,  metabolism*
Proto-Oncogene Proteins c-akt / genetics,  metabolism*
STAT5 Transcription Factor / metabolism*
Grant Support
ID/Acronym/Agency:
R01 CA098371/CA/NCI NIH HHS; U01 CA105490/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Milk Proteins; 0/STAT5 Transcription Factor; 9002-62-4/Prolactin; EC 2.7.11.1/Akt1 protein, mouse; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.1.3.48/Pten protein, mouse; EC 3.1.3.67/PTEN Phosphohydrolase
Comments/Corrections
Comment In:
Genes Dev. 2012 Oct 15;26(20):2253-8   [PMID:  23070811 ]

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