Michael B. Sporn

Bio: Michael B. Sporn is an academic researcher from Dartmouth College. The author has contributed to research in topics: Transforming growth factor & Transforming growth factor beta. The author has an hindex of 157, co-authored 559 publications receiving 94605 citations. Previous affiliations of Michael B. Sporn include Cornell University & Reata Pharmaceuticals.

The synthetic triterpenoid, CDDO-Imidazolide blocks nuclear factor-κB activation through direct inhibition of IκB kinase-beta.

Abstract: Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006 A94 Signaling cascades emanating from nuclear factor-kappaB (NF-κB) activation have been shown to play pivotal roles in the processes of tumor initiation, promotion, and progression. Inhibition of this pathway is in an attractive target for chemopreventive and chemotherapeutic agents. The synthetic triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) is a multifunctional agent with potent anti-inflammatory, anti-proliferative, cytoprotective, and apoptotic activities, whose molecular targets are unknown. Using both cell-free and cellular assays we show that CDDO-Im, at mid to high nM concentrations is a direct inhibitor of IκB kinase-beta (IKKβ), and that it thereby inhibits binding of nuclear factor-κB (NF-κB) to DNA and subsequent transcriptional activation. Pretreatment of cells with CDDO-Im prevents IκB alpha (IκBα) phosphorylation and degradation in response to tumor necrosis factor alpha (TNFα). The kinetics of this inhibition by CDDO-Im are rapid and occur with 15 minutes. A biotinylated analog of CDDO-Im showed that CDDO-Im binds to the IKK signalsome. Furthermore, we show that cysteine 179 on IKK is a target for CDDO-Im. This is the first report to demonstrate that this novel synthetic triterpenoid binds to and inhibits IKKβ directly. Due to the critical role played by NF-κB in tumor initiation, promotion, and progression, inhibition of IKKβ by this novel triterpenoid may play an important pharmacological role in its chemopreventive and chemotherapeutic capabilities. CDDO-Im is currently being evaluated as a chemopreventive agent in a number of preclinical disease models.

Autocrine TGFβ Synthesis by T47D Breast Cancer Cells in Response to a Novel Synthetic Progestin

Abstract: Recent experimental work has shown the existence of a previously undiscovered, highaffinity intracellular binding site for the synthetic progestin 17a-ethinyl-13P-ethyl-17p hydroxy-4,15-estradiene-3-one (gestodene) specific to breast cancer cells. This protein has a molecular weight of 45 to 50 K on nondissociating systems and is not attributable to any of the conventional classes of steroid hormone receptors or their proteolytic products. This new binding site has been found on all breast cancer cell lines tested so far regardless of the presence of estrogen and progesterone receptors. In a series of dose-response experiments, in vitro gestodene was found to be growth inhibitory for breast cancer cells in monolayer culture and the extent of this inhibition correlates with the intracellular concentration of the intracellular binding protein for gestodene. To test the hypothesis that gestodene might be elicting the synthesis of a negative growth modulator, the secretion of TGFP in response to gestodene, a range of other progestins, tamoxifen, dexarnethasone, and estradiol was investigated in serum-free monolayers of T47D breast cancer cells. The conditioned media from these cells were then concentrated, dialyzed, and acid-extracted prior to assay for total TCF(3. The results from the A549 cell radioreceptor assay are presented in TABLE 1. Antibody reversal experiments with specific polyclonal antibodies to TGFP subtypes 1 and 2 , used in the CCL64 bioassay, showed that the majority of the TGFP secreted was type 1, accounting for 60 to 70% of the total TGFP. The remainder was TGFP type 2. Immunoprecipitation of [3] metabolically labeled conditioned media from T47D cells confirmed these observations. Northern analysis indicates that the mechanism of this induction appears to be predominantly post-transcriptional. As gestodene is a potent progestin in wivo, the prospect of the chernoprevention of breast cancer via oral contraceptive use becomes an intriguing possibility.

Pyridyl analogs of 1-(2-cyano-3,12-dioxooleana-1,9(11)dien-28-oyl) imidazole

Abstract: Pyridyl analogs of 1-(2-cyano-3,12-dioxooleana- 1,9(11 ) -dien-28-oyl) imidazole and pharmaceutical compositions containing the same are provided. The present invention is a tnterpenoid compound of Formula I, or a hydrate, isomer, prodrug or pharmaceutically acceptabl salt thereof: wherein one or more of R, R or R is independently a substituted or unsubstituted aryl group, heteroaryl group, cycloalkyl group or heterocyclyl group, and the remaining R groups are hydrogen. The pyridyl analogs of CDDO-lm 1 have been developed, which are more stable in human plasma and achieve a higher concentration in target tissues such as liver, pancreas, kidney and lungs.

Transforming Growth Factor-β Production and Immunohistochemical Localization during Bleomycin-Induced Pulmonary Inflammationa

Abstract: Transforming growth factor-p (TGFP), a 25 kD homo-dimer and heterodimer is a multifunctional regulator of cell growth and differentiation! A number of previously described TGFP functions suggest a role in tissue repair. TGFP is a chemoattractant for monocytes and fibroblasts.' TGFP induces monocytes to secrete IL-1, a potent mitogen for fibroblasts, and by itself can stimulate proliferation of immature fibroblasts.' TGFP enhances synthesis of collagen, fibronectin, and proteoglycans.' In vivo TGFP stimulates granulation tissue, angiogenesis? and increased collagen synthesis? The pathogenesis of chronic pulmonary fibrosis is not well understood but based on animal models, the fibrotic response is preceded by an influx of inflammatory cells! Because of the well described effects of TGFP on inflammatory cells and connective tissue, we examined the relationship between collagen synthesis and TGFS production and distribution in a rat model of bleomycin-induced inflammation and fibrosis. Total lung TGFP was elevated 2 h after intratracheal bleomycin administration and peaked at 7 days (FIG. 1). TGFP gradually declined with persistent levels of production up to 28 days. Peak TGFP levels preceded the maximum collagen and non-collagen protein synthesis at 14 days by fibroblasts isolated from lung explants of bleomycintreated rats. Immunohistochemical staining localized TGFP initially in the cytoplasm of bronchiolar epithelium cells and the subepithelial extracellular matrix (FIG. 2). Peak lung TGFP levels at 7 days coincided with intense TGFP staining of scattered alveolar macrophages while subsequently TGFP-producing macrophages were found in organized clusters. After 7 days TGFP was primarily associated with extracellular matrix

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

The pathogenesis of atherosclerosis: a perspective for the 1990s

Abstract: Atherosclerosis, the principal cause of heart attack, stroke and gangrene of the extremities, is responsible for 50% of all mortality in the USA, Europe and Japan. The lesions result from an excessive, inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall. A large number of growth factors, cytokines and vasoregulatory molecules participate in this process. Our ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.

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.