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Biomedical subjects

M Azam

Publications and source records attributed to M Azam.

At least 37 records · Page 2Linked to original sources
PubMed1997

The beta2 subunit inhibits stimulation of the alpha1/beta1 form of soluble guanylyl cyclase by nitric oxide. Potential relevance to regulation of blood pressure.

Cytosolic guanylyl cyclases (GTP pyrophosphate-lyase [cyclizing; EC 4.6.1.2]), primary receptors for nitric oxide (NO) generated by NO synthases, are obligate heterodimers consisting of an alpha and a beta subunit. The alpha1/beta1 form of guanylyl cyclase has the greatest activity and is considered the universal form. An isomer of the beta1 subunit, i.e., beta2, has been detected in the liver and kidney, however, its role is not known. In this study, we investigated the function of beta2. Immunoprecipitation experiments showed that the beta2 subunit forms a heterodimer with the alpha1 subunit. NO-stimulated cGMP formation in COS 7 cells cotransfected with the alpha1 and beta2 subunits was approximately 1/3 of that when alpha1 and beta1 subunits were cotransfected. The beta2 subunit inhibited NO-stimulated activity of the alpha1/beta1 form of guanylyl cyclase and NO-stimulated cGMP formation in cultured smooth muscle cells. Our results provide the first evidence that the beta2 subunit can regulate NO sensitivity of the alpha1/beta1 form of guanylyl cyclase. Northern analysis for guanylyl cyclase subunits was performed on RNA from kidneys of Dahl salt-sensitive rats, which have been shown to have decreased renal sensitivity to NO. Compared to the Dahl salt-resistant rat, message for beta2 was increased, beta1 was decreased, and alpha1 was unchanged. These results suggest a molecular basis for decreased renal guanylyl cyclase activity, i.e. , an increase in the alpha1/beta2 heterodimer, and decrease in the alpha1/beta1 heterodimer.

Animals↗
PubMed1997

Functionally distinct isoforms of STAT5 are generated by protein processing.

The interleukin-3 family of cytokines, which play an important role in the development of myeloid lineages, transduce signals through the JAK-STAT pathway. Previous studies demonstrate that this process entails the activation of four distinct isoforms of STAT5, where two shorter isoforms are activated in a distinct population of cells. We now demonstrate that the shorter isoforms represent carboxy-terminal truncations. Moreover, these truncations are not generated by RNA processing, but by a specific proteolytic activity. Consistent with the notion that truncated STAT5 isoforms transduce distinct signals, they fail to promote the activation of several known interleukin-3 target genes. These studies suggest that the activity of a specific protease may play a critical role in defining the biological responses transduced by STAT5.

Cells, Cultured↗
PubMed1997

Symptomatic carriers of muscular dystrophy.

Data of twelve females who were symptomatic carriers of Duchenne muscular dystrophy is being reported here. Age at the time of presentation varied from one year to 17 years. All patients presented with progressive motor disability or delayed development. Six patients were bed ridden and 8 had history of similar disorder in male siblings. Majority of them had serum creatine kinase levels more than ten times the upper normal limit. Muscle biopsy was consistent with the diagnosis of muscular dystrophy in 4 patients and 1 patient had normal result. Overall prognosis was invariably poor.

Adolescent↗
PubMed1995

Eradication of dracunculiasis from Pakistan.

In 1986 the World Health Organization targeted dracunculiasis (Guinea-worm disease), which seriously impairs socioeconomic development in 16 African countries, India, Pakistan, and Yemen, to be eradicated globally. The target date for eradication by the end of 1995 was established in 1991. Pakistan eradicated dracunculiasis from the country in October, 1993, after a national campaign which began in 1987 with a nationwide village-by-village search for cases. The infection, which is transmitted by drinking water from ponds containing infected water fleas, was eradicated by using health education, cloth filters, and the cyclopsicide, temephos; and in the later stages, by case containment. Methods pioneered in Pakistan's National Guinea Worm Eradication Program are now being applied in remaining endemic countries.

Communicable Disease Control↗
PubMed1995

Interleukin-3 signals through multiple isoforms of Stat5.

The interleukin (IL)-3 family of cytokines mediates its numerous effects on myeloid growth and maturation by binding a family of related receptors. It has been shown recently that IL-3 induces the activation of two distinct cytoplasmic signal transducing factors (STFs) that are likely to mediate the induction of immediate early genes. In immature myeloid cells, IL-3 activates STF-IL-3a, which comprises two tyrosine-phosphorylated DNA binding proteins of 77 and 80 kDa. In mature myeloid cells, IL-3 and granulocyte-macrophage colony-stimulating factor activate STF-IL-3b, which consists of a 94 and 96 kDa tyrosine-phosphorylated DNA binding protein. Peptide sequence data obtained from the purified 77 and 80 kDa proteins (p77 and p80) indicate that they are closely related but are encoded by distinct genes. Both peptide and nucleotide sequence data demonstrate that these two proteins are the murine homologs of ovine mammary gland factor (MGF)/Stat5. The peptide data also indicate that p77 and p80 are phosphorylated on tyrosine 699, a position analogous to the tyrosine that is phosphorylated in Stat1 and Stat2 in response to interferon. Additionally, antiserum raised against bacterially expressed p77/p80 recognizes the 94 and 96 kDa protein components of STF-IL-3b, suggesting that these may be additional isoforms of Stat5. These studies indicate that the IL-3 family of ligands is able to activate multiple isoforms of the signal transducing protein Stat5.

Amino Acid Sequence↗
PubMed1995

A tumor-derived protein which provides T-cell costimulation through accessory cell activation.

A recently described tumor-derived glycoprotein, designated 90K, has been shown to have positive effects on the generation of cytotoxic effector cells (NK/LAK) from human PBMC. To determine the mechanism of these effects, we have examined the effects of 90K on cytokine production by human PBMC. A culture of normal PBMC with 90K alone did not result in IL-2 secretion; however, in coculture with suboptimal doses of ConA, 90K increased IL-2 secretion by PBMC. Coculture of PBMC with 90K and ConA also resulted in increased production of the cytokines IL-1, IL-6, GM-CSF, and TNF alpha. T cells depleted of accessory cells failed to respond to ConA alone, 90K alone, or the combination of ConA and 90K, suggesting that this protein does not have a direct effect on T cells. However, 90K alone was sufficient to induce cytokine production by unfractionated PBMC (IL-1, IL-6, GM-CSF, and TNF alpha) or by CD14-enriched PBMC (IL-1 and IL-6). In addition, expression of ICAM-1 was increased on a human monocytic cell line cultured with purified 90K in the absence of any other stimulus. This 90K-induced upregulation of ICAM-1 expression was accompanied by an increased accessory function of the monocytes, demonstrated by their ability to support ConA-induced activation of peripheral blood T cells. Based on the current data, we propose a model in which 90K activates accessory cells, resulting in the secretion of cytokines and the expression of adhesion molecules, which in turn act as costimulatory signals for T-cell activation. Activated T cells then produce cytokines such as IL-2, which lead to a more vigorous cell-mediated immune response to tumor cells and virus-infected cells. Thus, 90K shows promise as an immunotherapeutic reagent for diseases such as cancer and viral infection.

Antigen-Presenting Cells↗
PubMed1994

The secreted tumor-associated antigen 90K is a potent immune stimulator.

Immunization of mice with conditioned media from human breast cancer cells yielded the monoclonal antibody SP-2, which recognized an antigen of approximately 90-95 kDa. This protein, designated 90K, was found to be present in the serum of healthy individuals and at elevated levels in the serum of subpopulations of patients with various types of cancer and AIDS. Here we report the primary structure of the SP-2 antigen and demonstrate its relationship to a family of proteins which carry a scavenger receptor cysteine-rich domain. Northern blot analysis of normal tissues, primary tumors, and tumor-derived cell lines indicates a broad expression spectrum of the 90K gene at widely varying levels. Functional characterization reveals stimulatory effects of 90K on host defense systems, such as natural killer cell and lymphokine-activated killer cell activity, and indicates that its immunostimulatory effects may be mediated through the induction of interleukin-2 and possibly other cytokines.

3T3 Cells↗
PubMed1994

Cytokines and growth factors signal through tyrosine phosphorylation of a family of related transcription factors.

The ability of cytokines to activate distinct but overlapping sets of genes defines their characteristic biological response. We now show that IFN gamma, IL-3, IL-4, IL-6, erythropoietin, EGF, and CSF-1 activate differing members of a family of latent cytoplasmic transcription factors. Although these factors have distinct physical and functional properties and exhibit different patterns of expression, they share many important features, including recognition of a related set of enhancer elements, rapid activation, tyrosine phosphorylation, and cross-reactivity to antibodies against p91, a cytoplasmic signaling protein activated by IFN alpha, IFN gamma, and IL-6. These shared features point to either parallel or common patterns of signal transduction. A general model of cytokine signal transduction is presented, in which receptor-associated tyrosine kinases activate ligand-specific members of a family of signal-transducing factors. Once activated, these factors carry their signals to the nucleus, where they bind a family of related enhancer elements.

Base Sequence↗
PubMed1994

A 50 kDa protein present in conditioned medium of COLO-16 cells stimulates cell spreading and motility, and activates tyrosine phosphorylation of Neu/HER-2, in human SK-BR-3 mammary cancer cells.

A factor present in conditioned medium of COLO-16 human cancer cells causes fast spreading, fast plasma membrane ruffling, cell shape change, net translocation, stimulation of chemotaxis and growth arrest in human SK-BR-3 mammary cancer cells. Based on the spreading effect, the factor was purified to homogeneity and migrated as a 50 kDa protein in SDS-polyacrylamide gel electrophoresis. Addition of the purified 50 kDa factor to the target cells in culture results in tyrosine phosphorylation of the p185erbB2 receptor concomitant with a fast redistribution and clustering of the receptor. The 50 kDa factor is also specifically retained by affinity chromatography on the immobilized extracellular domain of p185erbB2. Antibodies directed against this domain also inhibit the induction of motility. These data suggest that the 50 kDa factor is a putative ligand of p185erbB2 in SK-BR-3 cells. Biochemical and immunological evidence further indicate that this factor differs from p185erbB2 ligands described so far. Its activity could play a role in the pathogenesis of breast cancer.

Animals↗
PubMed1992

Modulation of rat brain insulin receptor kinase activity in diabetes.

Insulin receptors from rat brain regions were studied for insulin binding and receptor associated kinase activity, in alloxan induced short-term and long-term diabetes, and insulin induced hypoglycemia. Insulin receptor activity was assessed by [125I]insulin binding, and basal as well as insulin stimulated kinase activity of the receptor, expressed as phosphorylation of the synthetic peptide poly (Glu-Tyr (4:1)). Regional distribution pattern elicited the highest binding and kinase activity in the olfactory bulb. Diabetes caused a significant increase in the kinase activity. The data suggests that brain insulin receptor kinase is regulated differently compared to peripheral tissues and supports the concept of an active brain insulin receptor in vivo.

Animals↗
PubMed1992

Effect of experimental diabetes on the catecholamine metabolism in rat brain.

The levels of epinephrine, norepinephrine, and dopamine and the activities of tyrosine hydroxylase and monoamine oxidase were estimated in four regions of rat brain during alloxan-induced hyperglycemia and insulin-induced hypoglycemia. Catecholamine levels were estimated by HPLC, and the insulin levels were quantified by radioimmunoassay. The results demonstrated significant increases in the activities of the metabolizing enzymes and levels of catecholamines during experimental conditions. The levels of catecholamines were highest in the cerebral hemispheres, the region associated with high activities of the metabolizing enzymes. Insulin-induced hypoglycemia caused a decrease in the activities of the metabolizing enzymes followed by their recovery within 2 h.

Animals↗