Abstract
STATs (signal transducer and activator of transcription) are a family of latent transcription factors which are activated in response to a variety of cytokines and growth factors. This family of signalling molecules have been implicated in growth, differentiation, survival and apoptosis. In this article, we will review work which highlights the role of individual STAT factors in mammary gland and demonstrate the value of genetically modified mice in defining the function of STAT3. Involution of the mouse mammary gland is characterised by extensive apoptosis of the epithelial cells and the activation of STAT3. STATs 3 and 5 have reciprocal patterns of activation throughout a mammary developmental cycle suggesting that STAT5 may be a survival factor and STAT3 a death factor for differentiated mammary epithelium. To clarify the role of STAT3 in mammary epithelial apoptosis, we have generated a conditional knockout using the lox/Cre recombination system. Mammary glands from crosses of transgenic mice expressing Cre recombinase under the control of the β-lactoglobulin milk protein gene promoter with mice harbouring one floxed STAT3 allele and one null STAT3 allele, showed a decrease in epithelial apoptosis and a dramatic delay of the involution process upon forced weaning. This was accompanied by precocious activation of STAT1 and increases in p53 and p21 levels — these may act as a compensatory mechanism for initiating the eventual involution which occurs in STAT3 null mammary glands. This demonstrates for the first time the importance of STAT factors in signalling the initiation of physiological apoptosis in vivo and highlights the utility of the lox/Cre system for addressing the function of genes, which have an embryonic lethal phenotype, specifically in mammary gland.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Weaver, VM and MJ Bissell 1999. Functional culture models to study mechanisms governing apoptosis in normal and malignant mammary epithelial cells J. Mam Gland Biol. & Neoplasia 4: 193–201.
Alexander CM, EW Howard, MJ Bissell, and Z Werb. 1996. Rescue of mammary epithelial cell apoptosis and entactin degradation by a tissue inhibitor of metalloproteinases-1 transgene. J. Cell Biol. 135: 1669–1677.
Neuenschwander, S., A. Schwart, T.L. Wood, C.T. Roberts Jr, L. Hennighausen and D. Le Roith. 1996. Involution of the lactating mammary gland is inhibited by the IGF system in a transgenic mouse model. J. Clin. Invest. 97: 2225–2232.
Ormandy, CJ, A Camus, J Barra, JD Damotte, B Lucas, H Buteau, M Edery, N Brousse, C Babinet, N Binart, and PA Kelly 1997. Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse Genes & Dev. 11: 167–178.
Watson, C.J., K.E. Gordon, M. Robertson, and A.J. Clarke 1991. Interaction of DNA-binding proteins with a milk protein gene promoter in vitro: identification of a mammary-specific factor. NUC. Acids Res. 19: 6603–6610.
Schmitt-Ney, M., W. Doppler, R.K. Ball, and B. Groner 1991. Beta-casein gene promoter activity is regulated by the hormone-mediated relief of transcriptional repression and a mammary gland-specific nuclear factor. Mol. Cell. Biol. 11: 3745–3755.
Wakao, H., F. Gouilleux, and B. Groner 1994. Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response. EMBO J. 13: 2182–2191.
Ihle, J.N. 1996. STATs: Signal transducers and activators oftranscription. Cell 84: 331–334.
Burdon, T.G., K. A. Maitland, A.J. Clark, R. Wallace and C. J. Watson 1994. Regulation of the sheep b-lactoglobulin gene by lactogenic hormones is mediated by a transcription factor that binds to an IFN-)g activation site-related element. Mol. Endo. 8 1528–1536.
Li, S. and J. M. Rosen 1995. Nuclear factor-1 and mammary gland factor (STATS) play a critical role in regulating rat whey acidic protein gene expression in transgenic mice. Mol.Cell. Biol 15: 2063–2070.
John, S, U. Vinkemeier, E Soldaini, JE Damell, and WJ Leonard 1999. The significance of tetramerization in promoter recruitment by Stat5. Mol. Cell. Biol. 19: 1910–1918.
Philp, J.C., T.G. Burdon, and C.J. Watson. 1996. Differential activation of STATs 3 and 5 during mammary gland development. FEBS Lett. 396: 77–80.
Liu, X.W., G.W. Robinson, and L. Hennighausen. 1996. Activation of Stat5a and Stat5b by tyrosine phosphorylation is tightly linked to mammary gland differentiation. Mol. Endocrinol. 10: 1496–1506.
Liu, X.W., G.W. Robinson, K.U. Wagner, L. Garrett, A. WynshawBoris, and L. Hennighausen. 1997. Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes & Dev. 11: 179–186.
Teglund, S., C. Mckay, E. Schuetz, J.M. van Deursen, D. Stravopodis, D.M. Wang, M. Brown, S. Bodner, G. Grosveld, and J.N. Ihle. 1998. Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 93: 841–850.
Takeda, K., K. Noguchi, W. Shi, T. Tanaka, M. Matsumoto, N. Yoshida, T. Kishimoto, and S. Akira. 1997. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc.Natl.Acad.Sci. U.S.A. 94: 3801–3804.
Niwa, H., T.G. Burdon, I. Chambers and A. G. Smith 1998. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes & Dev. 12: 2048–2060.
Rossant, J and A McMahon 1999. ”Cre„-ating mouse mutants—a meeting review on conditional mouse genetics Genes & Dev. 13: 142–145.
Selbert, S., D.J. Bentley, D.W. Melton, D. Rannie, P. Lourenco, C.J. Watson, and A.R. Clarke. 1998. Efficient BLG-Cre mediated gene deletion in the mammary gland. Transgenic Res. 7: 387–396.
Takeda, K., T. Kaisho, N. Yoshida, J. Takeda, T. Kishimoto, and S. Akira. 1998. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: Generation and characterization of T cell-specific Stat3-deficient mice. J lmmunol. 161: 4652–4660.
Chapman, R.S., P. Lourenco, E. Tonner, D. Flint, S. Selbert, K. Takeda, S. Akira, A.R. Clarke, and C.J. Watson 1999. Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of STAT3. Genes & Dev. 13: 2604–2616.
Watson, C.J. and W.R. Miller 1995. Elevated levels of members of the STAT family of transcription factors in breast carcinoma nuclear extracts. British J. Cancer 71: 840–844.
Garcia, R. and R. Jove 1998. Activation of STAT transcription factors in oncogenic tyrosine kinase signaling. J. Biomed. Sci. 5: 79–85.
Minami, M., M. Inoue, S. Wei, K. Takeda, M. Matsumoto, T. Kishimoto, and S. Akira. 1996. STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line. Proc.Natl.Acad.Sci. U.S.A. 93: 3963–3966
Fukada, T., M. Hibi, Y. Yamanaka, M. Takahashi, Y. Tezuka, T. Fujitani, T. Yamaguchi, K. Nakajima, and T. Hírano 1996. Two signals are necessary for cell. by a cytokine receptor gp130: Involvement of STAT3 in anti-apoptosis. Immunity -460.
Zamorano, J., H.Y. Wang, R. Wang, Y. Shi, G.D. Longmore, and A.D. Keegan. 1998. Regulation of cell growth by IL-2: Role of STAT5 in protection from apoptosis but not in cell cycle progression. J.Immunol. 160: 3502–3512.
Bovolenta, C., L. Testolin, L. Benussi, P.J. Lievens, and E. Liboi. 1998. Positive selection of apoptosis resistant cells correlates with activation of dominant negative STAT5. J Biol Chem. 273: 20779–20784.
Xu, X., K. Wagner, D. Larson, Z. Weaver, C. Li, T. Reid, L. Hennighausen, A. Wynshaw-Boris and C. Deng. 1999. Conditional mutation of Brcalin mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nature Gen. 22: 37–43.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Kluwer Academic Publishers
About this chapter
Cite this chapter
Chapman, R.S. et al. (2002). The Role of Stat3 in Apoptosis and Mammary Gland Involution. In: Mol, J.A., Clegg, R.A. (eds) Biology of the Mammary Gland. Advances in Experimental Medicine and Biology, vol 480. Springer, Boston, MA. https://doi.org/10.1007/0-306-46832-8_16
Download citation
DOI: https://doi.org/10.1007/0-306-46832-8_16
Publisher Name: Springer, Boston, MA
Print ISBN: 978-0-306-46414-0
Online ISBN: 978-0-306-46832-2
eBook Packages: Springer Book Archive