Role of serine phosphorylation of Stat5a in prolactin-stimulated beta-casein gene expression. Mol Cell Endocrinol 2001 Oct 25;183(1-2):151-63
Date
10/18/2001Pubmed ID
11604235DOI
10.1016/s0303-7207(01)00546-9Scopus ID
2-s2.0-0035950441 (requires institutional sign-in at Scopus site) 74 CitationsAbstract
Milk production remains suppressed in mammals during late pregnancy despite high levels of lactogenic polypeptide hormones. At parturition, associated with a precipitous fall in circulating progesterone, rising glucocorticoid levels synergize with prolactin to initiate copious milk production. This synergy is mediated at least in part through the coordinated activation of glucocorticoid receptors and transcription factor Stat5, particularly Stat5a. Here we show that two proline-juxtaposed serine residues within the transactivation domain of Stat5a are phosphorylated in the mammary gland during late gestation and lactation, and that these phosphorylation sites inhibit the transcriptional activity of Stat5a in the absence of glucocorticoid receptor costimulation. Specifically, transfection assays revealed that phosphorylation of residues S725 and S779 of Stat5a cooperatively suppressed prolactin-stimulated transcription from the beta-casein promoter in both COS-7 kidney and MCF-7 mammary cells. This suppression was associated with shortened duration and reduced amplitude of nuclear DNA binding activity of wild type Stat5a relative to that of the serine phosphorylation-defective Stat5 mutant. However, costimulation of glucocorticoid receptors completely reversed the suppressive effect of Stat5a serine phosphorylation on beta-casein gene transcription. We propose that serine phosphorylation within the transactivation domain may limit the activity of Stat5a in the absence of proper coactivation by glucocorticoid receptors.
Author List
Yamashita H, Nevalainen MT, Xu J, LeBaron MJ, Wagner KU, Erwin RA, Harmon JM, Hennighausen L, Kirken RA, Rui HMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAnimals
Caseins
Cattle
Cell Line
Culture Media, Serum-Free
DNA-Binding Proteins
Female
Gene Expression Regulation
Humans
Immunoblotting
Lactation
Mammary Glands, Animal
Mice
Mice, Inbred C57BL
Milk Proteins
Molecular Sequence Data
Phosphorylation
Phosphoserine
Pregnancy
Prolactin
Receptors, Glucocorticoid
STAT5 Transcription Factor
Sequence Alignment
Trans-Activators
Tumor Cells, Cultured
Tumor Suppressor Proteins