Lothar Hennighausen

Bio: Lothar Hennighausen is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Transcription factor & STAT5. The author has an hindex of 96, co-authored 316 publications receiving 31267 citations. Previous affiliations of Lothar Hennighausen include Chonnam National University & Dankook University.

Stat5a is mandatory for adult mammary gland development and lactogenesis.

Abstract: Prolactin (PRL) induces mammary gland development (defined as mammopoiesis) and lactogenesis. Binding of PRL to its receptor leads to the phosphorylation and activation of STAT (signal transducers and activators of transcription) proteins, which in turn promote the expression of specific genes. The activity pattern of two STAT proteins, Stat5a and Stat5b, in mammary tissue during pregnancy suggests an active role for these transcription factors in epithelial cell differentiation and milk protein gene expression. To investigate the function of Stat5a in mammopoiesis and lactogenesis we disrupted this gene in mice by gene targeting. Stat5a-deficient mice developed normally and were indistinguishable from hemizygous and wild-type littermates in size, weight, and fertility. However, mammary lobuloalveolar outgrowth during pregnancy was curtailed, and females failed to lactate after parturition because of a failure of terminal differentiation. Although Stat5b has a 96% similarity with Stat5a and a superimposable expression pattern during mammary gland development it failed to counterbalance for the absence of Stat5a. These results document that Stat5a is the principal and an obligate mediator of mammopoietic and lactogenic signaling.

Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system.

Abstract: Studies have focused on the events that influence the development of interleukin 17 (IL-17)–producing T helper cells (TH-17 cells) associated with autoimmunity, such as experimental autoimmune encephalitis, but relatively little is known about the cytokines that antagonize TH-17 cell effector responses. Here we show that IL-27 receptor–deficient mice chronically infected with Toxoplasma gondii developed severe neuroinflammation that was CD4+ T cell dependent and was associated with a prominent IL-17 response. In vitro, treatment of naive primary T cells with IL-27 suppressed the development TH-17 cells induced by IL-6 and transforming growth factor-β, which was dependent on the intracellular signaling molecule STAT1 but was independent of inhibition of IL-6 signaling mediated by the suppressor protein SOCS3. Thus IL-27, a potent inhibitor of TH-17 cell development, may be a useful target for treating inflammatory diseases mediated by these cells.

Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter

Abstract: Promoters whose temporal activity can be directly manipulated in transgenic animals provide a tool for the study of gene functions in vivo. We have evaluated a tetracycline-responsive binary system for its ability to temporally control gene expression in transgenic mice. In this system, a tetracycline-controlled trans-activator protein (tTA), composed of the repressor of the tetracycline-resistance operon (tet from Escherichia coli transposon Tn10) and the activating domain of viral protein VP16 of herpes simplex virus, induces transcription from a minimal promoter (PhCMV*-1; see below) fused to seven tet operator sequences in the absence of tetracycline but not in its presence. Transgenic mice were generated that carried either a luciferase or a beta-galactosidase reporter gene under the control of PhCMV*-1 or a transgene containing the tTA coding sequence under the control of the human cytomegalovirus immediate early gene 1 (hCMV IE1) promoter/enhancer. Whereas little luciferase or beta-galactosidase activity was observed in tissues of mice carrying only the reporter genes, the presence of tTA in double-transgenic mice induced expression of the reporter genes up to several thousand-fold. This induction was abrogated to basal levels upon administration of tetracycline. These findings can be used, for example, to design dominant gain-of-function experiments in which temporal control of transgene expression is required.

Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation.

Abstract: Cre-mediated excision of exon 11 of the breast-tumour suppressor gene Brca1 in mouse mammary epithelial cells causes increased apoptosis and abnormal ductal development. Mammary tumour formation occurs after long latency and is associated with genetic instability characterized by aneuploidy, chromosomal rearrangements or alteration of Trp53 (encoding p53) transcription. To directly test the role of p53 in Brca1-associated tumorigenesis, we introduced a Trp53-null allele into mice with mammary epithelium-specific inactivation of Brca1. The loss of p53 accelerated the formation of mammary tumours in these females. Our results demonstrate that disruption of Brca1 causes genetic instability and triggers further alterations, including the inactivation of p53, that lead to tumour formation.

Prospective identification of tumorigenic breast cancer cells

Abstract: Breast cancer is the most common malignancy in United States women, accounting for >40,000 deaths each year. These breast tumors are comprised of phenotypically diverse populations of breast cancer cells. Using a model in which human breast cancer cells were grown in immunocompromised mice, we found that only a minority of breast cancer cells had the ability to form new tumors. We were able to distinguish the tumorigenic (tumor initiating) from the nontumorigenic cancer cells based on cell surface marker expression. We prospectively identified and isolated the tumorigenic cells as CD44+CD24−/lowLineage− in eight of nine patients. As few as 100 cells with this phenotype were able to form tumors in mice, whereas tens of thousands of cells with alternate phenotypes failed to form tumors. The tumorigenic subpopulation could be serially passaged: each time cells within this population generated new tumors containing additional CD44+CD24−/lowLineage− tumorigenic cells as well as the phenotypically diverse mixed populations of nontumorigenic cells present in the initial tumor. The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival. Furthermore, because these cells drive tumor development, strategies designed to target this population may lead to more effective therapies.

TGF-beta signal transduction.

Abstract: The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-beta signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders.

Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.

Abstract: Approximately 10% of peripheral CD4+ cells and less than 1% of CD8+ cells in normal unimmunized adult mice express the IL-2 receptor alpha-chain (CD25) molecules. When CD4+ cell suspensions prepared from BALB/c nu/+ mice lymph nodes and spleens were depleted of CD25+ cells by specific mAb and C, and then inoculated into BALB/c athymic nude (nu/nu) mice, all recipients spontaneously developed histologically and serologically evident autoimmune diseases (such as thyroiditis, gastritis, insulitis, sialoadenitis, adrenalitis, oophoritis, glomerulonephritis, and polyarthritis); some mice also developed graft-vs-host-like wasting disease. Reconstitution of CD4+CD25+ cells within a limited period after transfer of CD4+CD25- cells prevented these autoimmune developments in a dose-dependent fashion, whereas the reconstitution several days later, or inoculation of an equivalent dose of CD8+ cells, was far less efficient for the prevention. When nu/nu mice were transplanted with allogeneic skins or immunized with xenogeneic proteins at the time of CD25- cell inoculation, they showed significantly heightened immune responses to the skins or proteins, and reconstitution of CD4+CD25+ cells normalized the responses. Taken together, these results indicate that CD4+CD25+ cells contribute to maintaining self-tolerance by down-regulating immune response to self and non-self Ags in an Ag-nonspecific manner, presumably at the T cell activation stage; elimination/reduction of CD4+CD25+ cells relieves this general suppression, thereby not only enhancing immune responses to non-self Ags, but also eliciting autoimmune responses to certain self-Ags. Abnormality of this T cell-mediated mechanism of peripheral tolerance can be a possible cause of various autoimmune diseases.

Photodynamic therapy for cancer

Abstract: The therapeutic properties of light have been known for thousands of years, but it was only in the last century that photodynamic therapy (PDT) was developed. At present, PDT is being tested in the clinic for use in oncology--to treat cancers of the head and neck, brain, lung, pancreas, intraperitoneal cavity, breast, prostate and skin. How does PDT work, and how can it be used to treat cancer and other diseases?

IL-17 and Th17 Cells.

Abstract: CD4+ T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided into Th1 or Th2 cells, depending on the cytokines they produce. A third subset of IL-17-producing effector T helper cells, called Th17 cells, has now been discovered and characterized. Here, we summarize the current information on the differentiation and effector functions of the Th17 lineage. Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the immune system. The differentiation factors (TGF-β plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORγt, and RORα) involved in the development of Th17 cells have just been identified. The participation of TGF-β in the differentiation of Th17 cells places ...