Essential functions of the Janus kinase 2 (Jak2) during mammary gland development and tumorigenesis
© BioMed Central 2005
Published: 17 June 2005
Jak2 is a hormone-receptor-coupled kinase that mediates the tyrosine phosphorylation and activation of signal transducers and activators of transcription (Stat). The biological relevance of Jak/Stat signaling in hormone-responsive adult tissues is difficult to investigate since Jak2 deficiency leads to embryonic lethality [1–3]. We therefore generated various Jak2 conditional knockout models to study essential functions of Jak2 during particular stages of mammary gland development and during neoplastic transformation in a Her2/neu-overexpressing breast cancer model. Our experiments show that Jak2 is essential for mammogenesis in virgin, pregnant, and postpartum females . In addition to its pivotal role for mammary epithelial cell proliferation, specification, and differentiation, we demonstrate that this kinase is indispensable for the prolactin-mediated activation of Stat5 and the maintenance of functionally differentiated alveolar cells during lactation. A primary focus of our current research is to examine how Jak/Stat signaling cascades are altered in breast cancer models that initiate tumorigenesis through overexpression of growth factor receptors, in particular ErbB2 (Her2/neu). The uniqueness of our model design enables us to genetically modify Jak/Stat signaling both prior to growth factor-mediated neoplastic transformation (cancer prevention) and during particular stages of the progressing disease (cancer therapy).
This work was supported, in part, by the Public Health Service grants CA93797 (to KUW) and CA101841 (to HR and KUW) from the National Cancer Institute. HR receives a Public Health Service grant from the National Institutes of Health (DK052013). AK received a stipend from the Deutsche Forschungsgemeinschaft (DFG, KR 2107/1-1). Support provided to KUW by the Nebraska Cancer and Smoking Disease Research Program (NE DHHS LB595), and the Cattlemen's Ball of Nebraska, Inc., was imperative to finance the generation of the Jak2-deficient animal model.
- Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, Vanin EF, Bodner S, Colamonici OR, van Deursen JM, et al: Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998, 93: 385-395. 10.1016/S0092-8674(00)81167-8.View ArticlePubMedGoogle Scholar
- Neubauer H, Cumano A, Muller M, Wu H, Huffstadt U, Pfeffer K: Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell. 1998, 93: 397-409. 10.1016/S0092-8674(00)81168-X.View ArticlePubMedGoogle Scholar
- Krempler A, Qi Y, Triplett AA, Zhu J, Rui H, Wagner KU: Generation of a conditional knockout allele for the Janus kinase 2 (Jak2) gene in mice. Genesis. 2004, 40: 52-57. 10.1002/gene.20063.View ArticlePubMedGoogle Scholar
- Wagner KU, Krempler A, Triplett AA, Qi Y, George NM, Zhu J, Rui H: Impaired alveologenesis and maintenance of secretory mammary epithelial cells in Jak2 conditional knockout mice. Mol Cell Biol. 2004, 24: 5510-5520. 10.1128/MCB.24.12.5510-5520.2004.View ArticlePubMedPubMed CentralGoogle Scholar