Inactivation of Stat5 in Mouse Mammary Epithelium During Pregnancy Reveals Distinct Functions in Cell Proliferation, Survival, and Differentiation

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2004 Sep 2

PMID 15340066

Citations 287

Authors

Yongzhi Cui

Greg Riedlinger

Keiko Miyoshi

Wei Tang

Cuiling Li

Chu-Xia Deng

Gertraud W Robinson

Lothar Hennighausen

Affiliations

Soon will be listed here.

Abstract

This study explored the functions of the signal transducers and activators of transcription 5a and 5b (referred to as Stat5 here) during different stages of mouse mammary gland development by using conditional gene inactivation. Mammary gland morphogenesis includes cell specification, proliferation and differentiation during pregnancy, cell survival and maintenance of differentiation throughout lactation, and cell death during involution. Stat5 is activated by prolactin, and its presence is mandatory for the proliferation and differentiation of mammary epithelium during pregnancy. To address the question of whether Stat5 is also necessary for the maintenance and survival of the differentiated epithelium, the two genes were deleted at different time points. The 110-kb Stat5 locus in the mouse was bracketed with loxP sites, and its deletion was accomplished by using two Cre-expressing transgenic lines. Loss of Stat5 prior to pregnancy prevented epithelial proliferation and differentiation. Deletion of Stat5 during pregnancy, after mammary epithelium had entered Stat5-mediated differentiation, resulted in premature cell death, indicating that at this stage epithelial cell proliferation, differentiation, and survival require Stat5.

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References

Liu X, Robinson G, Hennighausen L . Activation of Stat5a and Stat5b by tyrosine phosphorylation is tightly linked to mammary gland differentiation. Mol Endocrinol. 1996; 10(12):1496-506. DOI: 10.1210/mend.10.12.8961260. View

Moriggl R, Topham D, Teglund S, Sexl V, Mckay C, Wang D . Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity. 1999; 10(2):249-59. DOI: 10.1016/s1074-7613(00)80025-4. View

Wen X, Lin H, Shih H, Kung H, Ann D . Kinase activation of the non-receptor tyrosine kinase Etk/BMX alone is sufficient to transactivate STAT-mediated gene expression in salivary and lung epithelial cells. J Biol Chem. 1999; 274(53):38204-10. DOI: 10.1074/jbc.274.53.38204. View

Lord J, McIntosh B, Greenberg P, Nelson B . The IL-2 receptor promotes lymphocyte proliferation and induction of the c-myc, bcl-2, and bcl-x genes through the trans-activation domain of Stat5. J Immunol. 2000; 164(5):2533-41. DOI: 10.4049/jimmunol.164.5.2533. View

Seagroves T, Lydon J, Hovey R, Vonderhaar B, Rosen J . C/EBPbeta (CCAAT/enhancer binding protein) controls cell fate determination during mammary gland development. Mol Endocrinol. 2000; 14(3):359-68. DOI: 10.1210/mend.14.3.0434. View

Ormandy C, Binart N, Kelly P . Mammary gland development in prolactin receptor knockout mice. J Mammary Gland Biol Neoplasia. 2000; 2(4):355-64. DOI: 10.1023/a:1026395229025. View

Friedrichsen B, Galsgaard E, Nielsen J, Moldrup A . Growth hormone- and prolactin-induced proliferation of insulinoma cells, INS-1, depends on activation of STAT5 (signal transducer and activator of transcription 5). Mol Endocrinol. 2001; 15(1):136-48. DOI: 10.1210/mend.15.1.0576. View

Miyoshi K, Cui Y, Riedlinger G, Robinson P, Lehoczky J, Zon L . Structure of the mouse Stat 3/5 locus: evolution from Drosophila to zebrafish to mouse. Genomics. 2001; 71(2):150-5. DOI: 10.1006/geno.2000.6433. View

Ihle J . The Stat family in cytokine signaling. Curr Opin Cell Biol. 2001; 13(2):211-7. DOI: 10.1016/s0955-0674(00)00199-x. View

10.

Martin A, Fresno M . Regulation of nuclear factor kappa B transactivation. Implication of phosphatidylinositol 3-kinase and protein kinase C zeta in c-Rel activation by tumor necrosis factor alpha. J Biol Chem. 2001; 276(19):15840-9. DOI: 10.1074/jbc.M011313200. View

11.

Schwertfeger K, Richert M, Anderson S . Mammary gland involution is delayed by activated Akt in transgenic mice. Mol Endocrinol. 2001; 15(6):867-81. DOI: 10.1210/mend.15.6.0663. View

12.

Miyoshi K, Shillingford J, Smith G, Grimm S, Wagner K, Oka T . Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium. J Cell Biol. 2001; 155(4):531-42. PMC: 2198867. DOI: 10.1083/jcb.200107065. View

13.

Socolovsky M, Nam H, Fleming M, Haase V, Brugnara C, Lodish H . Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased survival of early erythroblasts. Blood. 2001; 98(12):3261-73. DOI: 10.1182/blood.v98.12.3261. View

14.

Ye S, Agata Y, Lee H, Kurooka H, Kitamura T, Shimizu A . The IL-7 receptor controls the accessibility of the TCRgamma locus by Stat5 and histone acetylation. Immunity. 2001; 15(5):813-23. DOI: 10.1016/s1074-7613(01)00230-8. View

15.

Walton K, Wagner K, Rucker 3rd E, Shillingford J, Miyoshi K, Hennighausen L . Conditional deletion of the bcl-x gene from mouse mammary epithelium results in accelerated apoptosis during involution but does not compromise cell function during lactation. Mech Dev. 2001; 109(2):281-93. DOI: 10.1016/s0925-4773(01)00549-4. View

16.

Cui Y, Li M, Walton K, Sun K, Hanover J, Furth P . The Stat3/5 locus encodes novel endoplasmic reticulum and helicase-like proteins that are preferentially expressed in normal and neoplastic mammary tissue. Genomics. 2001; 78(3):129-34. DOI: 10.1006/geno.2001.6661. View

17.

Snow J, Abraham N, Ma M, Abbey N, Herndier B, Goldsmith M . STAT5 promotes multilineage hematolymphoid development in vivo through effects on early hematopoietic progenitor cells. Blood. 2002; 99(1):95-101. DOI: 10.1182/blood.v99.1.95. View

18.

Bunting K, Bradley H, Hawley T, Moriggl R, Sorrentino B, Ihle J . Reduced lymphomyeloid repopulating activity from adult bone marrow and fetal liver of mice lacking expression of STAT5. Blood. 2002; 99(2):479-87. DOI: 10.1182/blood.v99.2.479. View

19.

Shillingford J, Miyoshi K, Robinson G, Grimm S, Rosen J, Neubauer H . Jak2 is an essential tyrosine kinase involved in pregnancy-mediated development of mammary secretory epithelium. Mol Endocrinol. 2002; 16(3):563-70. DOI: 10.1210/mend.16.3.0805. View

20.

Shillingford J, Miyoshi K, Flagella M, Shull G, Hennighausen L . Mouse mammary epithelial cells express the Na-K-Cl cotransporter, NKCC1: characterization, localization, and involvement in ductal development and morphogenesis. Mol Endocrinol. 2002; 16(6):1309-21. DOI: 10.1210/mend.16.6.0857. View