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T Zheng

Publications and source records attributed to T Zheng.

At least 109 records · Page 6Linked to original sources
PubMed1998

Differentially expressed GABAA-receptor subunits result in structurally and functionally receptor assemblies following excitatory afferent synaptic transmission.

Cerebellar granule cells isolated from postnatal day 7 rat pups are ideal for studying epigenetic events associated with the regulation of neuronal gene expression. These cultures contain from 90 to 95% glutamatergic granule cells and express mRNAs encoding a variety of ionotropic and metabotropic glutamate receptors as well as virtually all of the GABAA-receptor subunit mRNAs to different extents. A unique feature of this culture system is that the neurons undergo time-dependent maturation changes in vitro that mimic many of the characteristics of these receptors occurring in vivo. Granule cell cultures in vitro require depolarizing concentrations of KCl for long-term growth and survival. Both N-methyl-D-aspartate (NMDA) and GABA have been reported to exert trophic actions on these cells replacing the requirement for maintaining the cultures in high KCl. Cerebellar granule cells maintained under different conditions in vitro can be induced to alter their patterns of maturation, as indicated by the different temporal changes in gene expression of receptor subunit mRNAs and proteins. The focus of the current studies is the effect of NMDA afferent synaptic signaling on the changes in mRNA content and functional properties of GABAA receptors and how this may relate to comparable changes shown to occur in vivo.

Animals↗
PubMed1997

Regulation of the ribosome-membrane junction at early stages of presecretory protein translocation in the mammalian endoplasmic reticulum.

A series of fusion protein constructs were designed to investigate the contribution of secretory nascent chains to regulation of the ribosome-membrane junction in the mammalian endoplasmic reticulum. As a component of these studies, the membrane topology of the signal sequence was determined at stages of protein translocation immediately after targeting and before signal sequence cleavage. Truncated translation products were used to delimit the analysis to defined stages of translocation. In a study of secretory protein precursors, formation of a protease-resistant ribosome-membrane junction, currently thought to define the pathway of the translocating nascent chain, was observed to be precursor- and stage-dependent. Analysis of the binding of early intermediates indicated that the nascent chain was bound to the membrane independent of the ribosome, and that the binding was predominately electrostatic. The membrane topology of the signal sequence was determined as a function of the stage of translocation, and was found to be identical for all assayed intermediates. Unexpectedly, the hydrophobic core of the signal sequence was observed to be accessible to the cytosolic face of the membrane at stages of translocation immediately after targeting as well as stages before signal sequence cleavage. Removal of the ribosome from bound intermediates did not disrupt subsequent translocation, suggesting that the active state of the protein-conducting channel is maintained in the absence of the bound ribosome. A model describing a potential mode of regulation of the ribosome-membrane junction by the nascent chain is presented.

Animals↗
PubMed1997

Structure and folding of nascent polypeptide chains during protein translocation in the endoplasmic reticulum.

To investigate the role of protein folding and chaperone-nascent chain interactions in translocation across the endoplasmic reticulum membrane, the translocation of wild type and mutant forms of preprolactin were studied in vivo and in vitro. The preprolactin mutant studied contains an 18-amino acid substitution at the amino terminus of the mature protein, eliminating a disulfide-bonded loop domain. In COS-7 cells, mutant prolactin accumulated in the endoplasmic reticulum as stable protein-protein and disulfide-bonded aggregates, whereas wild type prolactin was efficiently secreted. In vitro, wild type and mutant preprolactin translocated with equal efficiency although both translation products were recovered as heterogeneous aggregates. Studies with translocation intermediates indicated that aggregation occurred co-translationally. To evaluate the contribution of lumenal chaperones to translocation and folding, in vitro studies were performed with native and reconstituted, chaperone-deficient membranes. The absence of lumenal chaperones was associated with a decrease in translocation efficiency and pronounced aggregation of the translation products. These studies suggest that chaperone-nascent chain interactions significantly enhance translocation and indicate that in the absence of such interactions, aggregation can serve as the predominant in vitro protein folding end point. The ramifications of these observations on investigations into the mechanism of translocation are discussed.

Amino Acid Sequence↗
PubMed1997

The increase of Hodgkin's disease incidence among young adults. Experience in Connecticut, 1935-1992.

BACKGROUND: Recent studies have indicated an increase in young adulthood Hodgkin's disease incidence, particularly among females, since 1970. However, no studies have examined the long term trends and period-cohort patterns of Hodgkin's disease incidence. METHODS: The current study reported time trends and age-period-cohort patterns of Hodgkin's disease incidence during the period 1935-1992, with an emphasis on incidence rate changes among young adults, using data from the Connecticut Tumor Registry. RESULTS: A total of 4997 incidences of Hodgkin's disease were included in the study. The authors found that the incidence of Hodgkin's disease had increased among young adults age 20-44 years. Incidence had increased dramatically among females since 1970 but less significantly among males. These observed trends were primarily associated with nodular sclerosis histologic type. Age-period-cohort analyses indicated that these observed increases in young adults were cohort phenomena, suggesting possible changes in exposure to risk factors. CONCLUSIONS: Currently identified major risk factors, including social status, Epstein-Barr virus infection, and human immunodeficiency virus infection, cannot adequately explain the observed trends. Analytical epidemiologic studies are urgently needed to identify risk factors that will not only elucidate the etiology of Hodgkin's disease but also explain the rapid increase in Hodgkin's disease incidence among young females.

Adult↗
PubMed1997

Cytokine signaling through the novel tyrosine kinase RAFTK in Kaposi's sarcoma cells.

A number of cytokines, including basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), oncostatin M (OSM), IL-6, and tumor necrosis factor alpha (TNF-alpha), have been postulated to have a role in the pathogenesis of Kaposi's sarcoma (KS). The proliferative effects of bFGF and OSM may be via their reported activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway in KS cells. We now report that KS cells express a recently identified focal adhesion kinase termed RAFTK which appears in other cell systems to coordinate surface signals between cytokine and integrin receptors and the cytoskeleton as well as act downstream to modulate JNK activation. We also report that the tyrosine kinase receptor FLT-4, present on normal lymphatic endothelium, is robustly expressed in KS cells. Treatment of KS cells with VEGF-related protein (VRP), the ligand for the FLT-4 receptor, as well as with the cytokines bFGF, OSM, IL-6, VEGF, or TNF-alpha resulted in phosphorylation and activation of RAFTK. Following its activation, there was an enhanced association of RAFTK with the cytoskeletal protein paxillin. This association was mediated by the hydrophobic COOH-terminal domain of the kinase. Furthermore, JNK activity was increased in KS cells after VEGF or VRP stimulation. We postulate that in these tumor cells RAFTK may be activated by a diverse group of stimulatory cytokines and facilitate signal transduction to the cytoskeleton and downstream to the growth promoting JNK pathway.

Animals↗
PubMed1997

Identification of a novel stage of ribosome/nascent chain association with the endoplasmic reticulum membrane.

Protein translocation in the mammalian endoplasmic reticulum (ER) occurs cotranslationally and requires the binding of translationally active ribosomes to components of the ER membrane. Three candidate ribosome receptors, p180, p34, and Sec61p, have been identified in binding studies with inactive ribosomes, suggesting that ribosome binding is mediated through a receptor-ligand interaction. To determine if the binding of nascent chain-bearing ribosomes is regulated in a manner similar to inactive ribosomes, we have investigated the ribosome/nascent chain binding event that accompanies targeting. In agreement with previous reports, indicating that Sec61p displays the majority of the ER ribosome binding activity, we observed that Sec61p is shielded from proteolytic digestion by native, bound ribosomes. The binding of active, nascent chain bearing ribosomes to the ER membrane is, however, insensitive to the ribosome occupancy state of Sec61p. To determine if additional, Sec61p independent, stages of the ribosome binding reaction could be identified, ribosome/nascent chain binding was assayed as a function of RM concentration. At limiting RM concentrations, a protease resistant ribosome-membrane junction was formed, yet the nascent chain was salt extractable and cross-linked to Sec61p with low efficiency. At nonlimiting RM concentrations, bound nascent chains were protease and salt resistant and cross-linked to Sec61p with higher efficiency. On the basis of these and other data, we propose that ribosome binding to the ER membrane is a multi-stage process comprised of an initial, Sec61p independent binding event, which precedes association of the ribosome/nascent chain complex with Sec61p.

Animals↗
PubMed1997

Glucocorticoids induce Kaposi's sarcoma cell proliferation through the regulation of transforming growth factor-beta.

Glucocorticoid (GC) use is known to induce or enhance the growth of Kaposi's sarcoma (KS) in many clinical settings including human immunodeficiency virus infection, collagen vascular disease, lymphoproliferative disorders, and renal transplantation. Because GCs may induce immune suppression and thus tumor growth, we determined whether GCs had a direct effect on KS growth. We found that GCs directly induce the growth of KS cell lines. In examining the mechanism of action of GCs, we did not observe induction of known autocrine growth factors for KS including interleukin-1 (IL-1), IL-6, oncostatin-M, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF). We thus examined factor(s) that inhibit KS growth. Transforming growth factor-beta (TGF-beta) is produced by KS cells and has pleiotropic effects, including inhibiting the growth of hematopoietic and endothelial cells. We show that TGF-beta is produced by KS cells in both the latent and active forms, and that TGF-beta is an autocrine growth inhibitory factor. We then studied the effects of GCs on the regulation of TGF-beta and found that GCs do not inhibit TGF-beta transcription, but significantly inhibit TGF-beta activation. This effect is mediated through regulation of the TGF-beta activation pathway. TGF-beta is activated by plasmin which is positively regulated by plasminogen activator (PA) and PA receptor (PAR), and negatively regulated by plasminogen activator inhibitor (PAI). GCs downregulated PAR and upregulated PAI. Thus, glucocorticoids enhance KS cell growth through the regulation of TGF-beta activation.

Cell Division↗
PubMed1997

Vascular endothelial growth factor/vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma.

Kaposi sarcoma (KS) is the most common tumor associated with HIV-1 infection and develops in nearly 30% of cases. The principal features of this tumor are abnormal vascularization and the proliferation of endothelial cells and spindle (tumor) cells. KS-derived spindle cells induce vascular lesions and display enhanced vascular permeability when inoculated subcutaneously in the nude mouse. This finding suggests that angiogenesis and capillary permeability play a central role in the development and progression of KS. In this study, we show that AIDS-KS cell lines express higher levels of vascular endothelial growth factor/vascular permeability factor (VEGF/VGF) than either human umbilical vein endothelial cells or human aortic smooth muscle cells. AIDS-KS cells and primary tumor tissues also expressed high levels of Flt-1 and KDR, the receptors for VEGF, while the normal skin of the same patients did not show any expression. We further demonstrate that VEGF antisense oligonucleotides AS-1 and AS-3 specifically block VEGF mRNA and protein production and inhibit KS cell growth in a dose-dependent manner. Furthermore, growth of KS cells in nude mice was specifically inhibited by VEGF antisense oligonucleotides. These results show that VEGF is an autocrine growth factor for AIDS-KS cells. To our knowledge, this is the first report that shows that VEGF acts as a growth stimulator in a human tumor. Inhibitors of VEGF or its cognate receptors may thus be candidates for therapeutic intervention.

AIDS-Related Opportunistic Infections↗
PubMed1997

Time trend of female breast carcinoma in situ by race and histology in Connecticut, USA.

A rapid increase of female breast cancer has been reported in many areas of the world and the reasons are not fully understood. While some have attributed the increase to the increasing detection of early stage breast cancer through mammography screening, few studies have directly examined the time trend of in situ breast cancer specifically. This study included all incident cases of female breast carcinoma in situ reported to the Connecticut Tumor Registry between 1973 and 1992. The age-adjusted incidence rates and age-specific incidence rates were calculated by histology and by race. The age-adjusted incidence rates were standardised to the 1970 United States standard million population. The study found that the overall age-adjusted incidence rate of in situ breast cancer has increased dramatically, from 3.53/100000 in 1973-1975 to 17.51/100000 in 1991-1992. The increase was not uniform during the past two decades of cancer registration. In fact, most of the observed rise has occurred since the early 1980s. This increase was found in both Caucasians and Blacks. The results by histology indicate that the dramatic increase in carcinoma in situ is mostly attributable to an increase in ductal carcinoma in situ. The increase was also observed in all age groups 40 years and over. These results are consistent with the use pattern and the reported effect of mammography screening. Therefore, these results are qualitatively consistent with the idea that mammography screening is largely responsible for the recent upsurge in female breast cancer incidence in this population. The study also found that the age group 40-49 years in whites experienced a rapid increase in incidence that began in the same time period as the older age groups, but it has since levelled off. The potential impact of the highly publicized debate regarding the efficacy of mammography in this age group in recent years is discussed.

Adult↗
PubMed1997

Risk of tongue cancer associated with tobacco smoking and alcohol consumption: a case-control study.

Recent studies indicate that cancer of the tongue is increasing rapidly among the younger population in many parts of the world. Few studies, however, have directly examined the risk factors for the disease. A case-control study was conducted in Beijing, China to investigate risk factors for tongue cancer. A total of 111 cases and 111 controls aged 20-80 years were included in this study. The results show that risk of tongue cancer is significantly elevated among ex-smokers (OR = 2.24, 95% CI = 1.09-4.62) and among current smokers (OR = 2.73, 95% CI = 1.26-5.91). The risk increases with increasing tobacco consumption, as reflected by both cigarette equivalents smoked per day and lifetime pack-years of tobacco smoking. Quitting smoking was associated with a reduction of the risk of tongue cancer. The numbers of cases in the study, however, is small, preventing further analyses during the years after quitting smoking. Overall, alcohol drinking was not found to be significantly associated with the risk of tongue cancer in this study (OR = 1.20, 95% CI = 0.58-2.50 for current drinkers). However, a marginally significant association was found for those who drank spirits at least 5 days a week (OR = 2.34, 95% CI = 0.90-6.06). A suggestion of effect modification for smoking and alcohol drinking was observed in this study.

Adult↗
PubMed1997

IL-4R expression in AIDS-KS cells and response to rhIL-4 and IL-4 toxin (DAB389-IL-4).

Interleukin-4 (IL-4) is a pleiotropic cytokine affecting growth and differentiation of various cell types as well as regulating other cytokines. To study the effect of IL-4 on AIDS-related Kaposi's sarcoma (AIDS-KS) cells, we first examined the tumor cells for IL-4 receptor (IL-4R) expression. KS cells express a single 4 kB IL-4R-specific mRNA and 1828 +/- 408 high affinity IL-4 binding sites per cell with a dissociation constant (Kd) of 154 +/- 37 pM. Addition of recombinant human IL-4 (rIL-4) minimally inhibited AIDS-KS cell growth and expression of IL-6. We then studied the effects of a chimeric fusion toxin DAB389-IL-4 which exerts cellular toxicity only on cells expressing IL-4R. DAB389-IL-4 inhibited protein synthesis in AIDS-KS cells at low concentrations (IC50 of 5 x 10(-11) M). This effect was abrogated by neutralizing antibody to IL-4 (25D2). We conclude that KS cells express a functional IL-4R and this receptor could serve as a target for novel therapy with agents such as DAB389-IL-4.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Comparison of organochlorine pesticide and polychlorinated biphenyl residues in human breast adipose tissue and serum.

The presence of organochlorine pesticides, such as p,p'-DDT[2,2-bis(p-chlorophenyl)-1,1,1-trichloroethanel, and of polychlorinated biphenyls (PCBs) in human serum and adipose tissue has been reported in many studies over the last four decades. Recently, debate has heightened concerning the link of these compounds to breast cancer. To clarify and resolve this issue, accurate analytical residue data must be obtained. Separation of the organochlorine pesticides from the PCBs in breast tissue is critical to obtaining valid residue data. Based on methods refined in the Analytical Laboratory at Colorado State University, accurate residue levels were established for nine individual PCB congeners and eight organochlorine pesticides. The breast adipose tissue method used was a modification of the Mills et al. and de Faubert Maunder et al. methods. The serum method employed was a modification of the Burse et al. method. Both breast adipose tissue and serum from 36 women were analyzed, and correlations of the residues from the two substrates were evaluated. Serum concentrations of p,p'-DDE, the primary metabolite of p,p'-DDT, were correlated (alpha = .05) with the concentrations of p,p'-DDE in human breast adipose tissue (r = .808). Serum concentrations of the PCB congener BZ 153 were also significantly correlated to the human breast adipose tissue concentrations of BZ 153 (r = .377). No significant relationship was found between serum concentrations and tissue residues for 15 of the 17 compounds analyzed. This lack of correlation between breast adipose tissue and serum, as well as an absence of the compound residues in serum, emphasized that adipose tissue should be analyzed in addition to serum to fully understand the relationship of the organochlorine compounds to breast cancer.

Adipose Tissue↗
PubMed1997

Are cancers of the salivary gland increasing? Experience from Connecticut, USA.

BACKGROUND: Recent studies indicate that cancers of the salivary gland are increasing, and the factors responsible for the increase are unknown. Artefactual changes, such as shift in classifying cancers of the floor of the mouth to cancers of the salivary gland, could affect the time trend for salivary gland cancer. METHODS: The current study examined the time trends for cancers of the salivary gland and for cancers of the floor of the mouth and lower gum by using Connecticut Tumor Registry data for the time period 1935-1992. A regression model was used to identify the components of birth cohort, period and age as determinants of the observed time trend. RESULTS: Cancers of the salivary gland have recently increased in Connecticut, with a relative risk of 1.48 (95% CI: 1.06-2.08) for females in 1990-1992 compared to 1980-1984, and a comparable relative risk of 1.60 (95% CI: 1.16-2.22) for males. The increase was found in all age groups 40 and over, particularly among those aged 70 and over. The results from age-period-cohort modelling show a recent upturn in the trend for period slopes, with no clear increase from recent birth cohorts, which is consistent with the results from univariate analyses suggesting no clear increase among those under 40 years of age. CONCLUSION: Our results suggest that artifactual changes, such as a shift in designation of cancer sites, increasing use of the needle aspirate biopsies, and greater access to medical care for the elderly, may have largely contributed to the rising trend. The known risk factors, radiation exposure and a history of a prior cancer, can hardly explain the observed increase. The Epstein-Barr virus infection has only been associated with certain types of rare squamous cell carcinomas of the salivary gland in the Eskimo population. The AIDS epidemic also cannot explain why older age groups have accounted for most of the increase in incidence of the disease. An examination of the incidence rates for cancers of the salivary gland from other populations may help to clarify the issue.

Adult↗
PubMed1997

Treatment of epidemic (AIDS-related) Kaposi's sarcoma.

Kaposi's sarcoma (KS) is the most common tumor seen in patients with HIV-1 infection. KS causes significant morbidity and mortality through involvement of the skin and visceral organs. The optimal treatment for KS depends on the extent of the disease and immunologic status. However, with knowledge gained on the pathogenesis of disease, newer therapies and compounds are being developed. Early disease patients are best treated with either local therapy or agents that have low toxicity and can be delivered long term. Advanced disease, such as in patients with widespread mucocutaneous disease, lymphedema, and visceral disease, are treated most effectively with cytotoxic agents such as liposomal anthracyclines, vinca alkaloids, or paclitaxel. Future treatment developments are focusing on the role of effective anti-HIV therapy and anti-human herpesvirus (HHV)-8 therapy in an effort to interfere with key steps in the etiology of KS to control the disease. Secondly, agents that focus on the interruption of autocrine and paracrine growth factors such as vascular endothelial cell growth factor and basic fibroblast growth factor, interleukin-6, and interleukin-8 are of therapeutic interest. Some of these compounds currently under evaluation include antiangiogenesis inhibitors and retinoids.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Retinoid antagonism of NF-IL6: insight into the mechanism of antiproliferative effects of retinoids in Kaposi's sarcoma.

All-trans-retinoic acid (RA) is active in the treatment of Kaposi's sarcoma (KS), and retinoids inhibit KS cell growth in vitro. To understand the mechanism of retinoid action in KS, we studied the expression of autocrine growth factors of KS cells after RA treatment. We demonstrate that RA and its synthetic analogs inhibit the proliferation of KS cells by inhibiting the mRNA and protein levels of interleukin-6 (IL-6), an autocrine growth factor for KS cells. We further demonstrate that nuclear retinoid receptors (RA receptors [RARs] and retinoid X receptors [RXRs]) inhibit IL-6 promoter action by antagonizing the enhancer action of NF-IL6, a basic domain leucine zipper transcription factor belonging to the family of CAAT enhancer binding proteins. Furthermore, RARs and RXRs do not bind in vitro to an NF-IL6 binding site. However, the secondary folded structure of the DNA binding domain of RAR and RXR is obligatory for inhibiting NF-IL6 activity. Thus, NF-IL6 is a potential therapeutic target for the treatment of KS. Finally, using receptor-selective synthetic retinoids, we demonstrate that NF-IL6 antagonism and transactivation are separable functions of RAR alpha, thus indicating that synthetic retinoids with properties of NF-IL6 antagonism but lacking transactivation capabilities can be synthesized. Such retinoids might increase therapeutic potential in KS.

CCAAT-Enhancer-Binding Proteins↗
PubMed1997

Phenotypic characterization and functional correlation of alpha-MSH binding to pituitary cells.

It is clear that alpha-melanocyte-stimulating hormone (alpha-MSH), released by the hypophysial neurointermediate lobe, is a mediator of suckling-induced prolactin release, but several questions surrounding its role remain unresolved. Accordingly, the objectives of the present study were 1) to establish whether alpha-MSH could bind in a reversible manner to a specific secretory type cell within the adenohypophysis (AP), 2) to resolve the issue of whether the peptide could compete with dopamine for the same receptor binding site, and 3) to seek a functional signaling correlate for alpha-MSH binding. In pursuit of these objectives, we subjected pituitary cells from lactating rats to alpha-MSH receptor autoradiography, AP hormone immunocytochemistry, or digital imaging fluorescence microscopy with fura 2 as a calcium-sensitive probe. Our results show that alpha-MSH binding is restricted to mammotropes and that a specific subpopulation of these express functional alpha-MSH receptors that are coupled to a Ca2+ signaling pathway. Moreover, alpha-MSH does not compete with dopamine antagonists/agonists for the same binding site.

Animals↗