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.

Sequence-specific 1H-NMR assignments and identification of two small antiparallel beta-sheets in the solution structure of recombinant human transforming growth factor alpha

Abstract: Transforming growth factor alpha (TGF alpha) is a small mitogenic protein with about 35% sequence identity with epidermal growth factor (EGF). TGF alpha-like proteins have been proposed to play a role in oncogenesis and wound healing. This report describes sequence-specific 1H-NMR resonance assignments for recombinant human TGF alpha (hTGF alpha). These assignments provide the basis for interpreting NMR data which demonstrate that the solution structure of hTGF alpha includes an antiparallel beta-sheet involving residues Gly-19 to Leu-24 and Lys-29 to Cys-34 and a second, smaller, antiparallel beta-sheet involving residues Tyr-38 and Val-39 and His-45 and Ala-46. These data, together with constraints imposed by the disulfide bonds, are combined to construct a molecular model of the polypeptide chain fold for residues Cys-8 to Ala-46. The resulting structure is similar to that of mouse and human EGF. Human TGF alpha and mouse EGF, however, differ with respect to their structural dynamics, since amide proton/deuteron exchange is much faster for hTGF alpha than for mouse EGF at pH 3.5.

Novel inhibitors of matrix metalloproteinase gene expression as potential therapies for arthritis.

Abstract: Matrix metalloproteinases are a family of endopeptidases that collectively degrade all components of the extracellular matrix at neutral pH. During the progression of arthritis, MMPs mediate the degradation of cartilage, which consists largely of Type II collagen fibrils and proteoglycans. The collagenases, a subgroup of MMPs, have the singular ability to cleave intact collagens and may provide a rate-limiting step in cartilage destruction. In arthritic lesions, collagenase-1 (matrix metalloproteinase-1) and collagenase-3 (matrix metalloproteinase-13) mediate the irreversible destruction of cartilage, suggesting that these enzymes are therapeutic targets. We describe the role of metalloproteinases in the destruction of connective tissues in arthritis and the treatment strategies that have been developed to block matrix metalloproteinases in an attempt to prevent this destruction. We also discuss novel compounds that may selectively inhibit these cartilage-degrading enzymes, providing opportunities to develop new therapeutic approaches.

Ultrastructural effects of N‐methyl‐N‐nitrosourea on the tracheobronchial epithelium of the Syrian Golden hamster

Abstract: Ten intratracheal instillations of N-methyl-N-nitrosourea (NMU) caused squamous metaplastic and neoplastic changes in the tracheobronchial epithelium. Abnormal squamous metaplastic cells contained enlarged nuclei deeply indented by cytoplasmic invaginations, pleomorphic nucleoli, filamentous granules and many cytoplasmic fibrils. Prior to the appearance of tumors, autoradiograms revealed cells preparing for division, first in basal and then in all layers of the abnormal squamous metaplastic epithelium. Defects in the basement lamina were found in squamous metaplastic lesions. The ultrastructural changes in the tracheobronchial epithelium were similar to those described in hamsters exposed to benzo[a]pyrene-ferric oxide as well as to those described in smoking dogs and in human bronchogenic carcinoma. The squamous metaplastic changes induced by NMU were clearly distinguishable from squamous metaplasia found in vitamin-A deficiency.

Sequence specific protein binding to and activation of the TGF-β3 promoter through a repeated TCCC motif

Abstract: We have previously characterized the TGF-beta 3 promoter and shown that the activity of this promoter is highly variable in different cell types. Although the promoter contains a proximal cAMP responsive element, which is critical to basal and forskolin-induced promoter activity, this element is not responsible for the variable, cell-specific regulation of the promoter. In this paper, we identify a 25 base pair sequence in the proximal region of the TGF-beta 3 promoter that binds a novel DNA-binding protein. This region includes the sequence T-CCCTCCCTCCC, (3 x TCCC), and mutation of these T-CCC repeats inhibits protein binding. Further, we show that in the cell line A375, which we have previously shown expresses high levels of TGF-beta 3 mRNA, this region is responsible for mediating high level TGF-beta 3 promoter activity. Immediately 3' to the 3 x TCCC sequence is a consensus AP-2 binding site, however, we show that this region does not bind AP-2, and AP-2 does not transactivate the TGF-beta 3 promoter. Therefore, we provide strong evidence that high level expression of TGF-beta 3 in A375 cells results from transactivation of the TGF-beta 3 promoter by a protein that binds to a repeated TCCC motif in the promoter and suggest that this DNA-binding protein likely also regulates aspects of developmental and tissue-specific expression of this cytokine.

Histogenesis of Induced Prostate and Seminal Vesicle Carcinoma in Lobund-Wistar Rats: A System for Histological Scoring and Grading

Abstract: We have developed a grading system for the evaluation of the histogenesis of neoplastic lesions of the prostate and seminal vesicle of the laboratory rat. Prostatic and seminal vesicle carcinomas were induced in Lobund-Wistar rats by initiation with 30 mg/kg N-nitroso-N-methylurea i.v., followed by promotion with 40 mg testosterone propionate implants 1 week later and at 3-month intervals thereafter. Experimental and control groups were sacrificed at various time points between 5 and 11 months after dosing with N-nitroso-N-methylurea in order to visualize progressive stages of carcinogenesis of the dorsolateral prostate, the anterior prostate, and the seminal vesicle. A system of staging was created which allows three different categories (in situ change, invasion, desmoplasia) of tumor development to be ranked progressively in a manner conducive to nonparametric analysis. Each category was then further subdivided to create a total of six stages. This system can be used to evaluate agents which modify tumor induction or suppression. The application of this staging system to the measurement of the effects of the synthetic retinoid, 4-hydroxyphenyl retinamide, on prostatic carcinogenesis in the Lobund-Wistar rat is described.

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.