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T Yin

Publications and source records attributed to T Yin.

35 records · Page 2Linked to original sources
PubMed1997

Tissue-specific pattern of stress kinase activation in ischemic/reperfused heart and kidney.

In this report we investigate the molecular mechanisms that contribute to tissue damage following ischemia and ischemia coupled with reperfusion (ischemia/reperfusion) in the rat heart and kidney. We observe the activation of three stress-inducible mitogen-activated protein (MAP) kinases in these tissues: p38 MAP kinase and the 46- and 55-kDa isoforms of Jun N-terminal kinase (JNK46 and JNK55). The heart and kidney show distinct time courses in the activation of p38 MAP kinase during ischemia but no activation of either JNK46 or JNK55. These two tissues also respond differently to ischemia/reperfusion. In the heart we observe activation of JNK55 and p38 MAP kinase, whereas in the kidney all three kinases are active. We also examined the expression pattern of two stress-responsive genes, c-Jun and ATF3. Our results indicate that in the heart both genes are induced by ischemia and ischemia/reperfusion. However, in the kidney c-Jun and ATF3 expression is induced only by ischemia/reperfusion. To correlate these molecular events with tissue damage we examined DNA laddering, a common marker of apoptosis. A significant increase in DNA laddering was evident in both heart and kidney following ischemia/reperfusion and correlated with the pattern of kinase activation, supporting a link between stress kinase activation and apoptotic cell death in these tissues.

Activating Transcription Factor 2↗
PubMed1997

Molecular characterization of specific interactions between SHP-2 phosphatase and JAK tyrosine kinases.

Interactions between SHP-2 phosphotyrosine phosphatase and JAK tyrosine kinases have recently been implicated in cytokine signal transduction. However, the molecular basis of these interactions is not well understood. In this study, we demonstrate that SHP-2 is tyrosine-phosphorylated by and associated with JAK1 and JAK2 but not JAK3 in COS-1 cell cotransfection experiments. SHP-2 phosphatase activity appears not to be required for JAK and SHP-2 interactions because SHP-2 with a mutation at amino acid 463 from Cys to Ser, which renders SHP-2 inactive, can still bind JAKs. We further demonstrate that SHP-2 SH2 domains (amino acids 1-209) are not essential for the association of JAKs with SHP-2, and the region between amino acids 232 and 272 in SHP-2 is important for the interactions. Furthermore, tyrosine residues 304 and 327 in SHP-2 are phosphorylated by JAKs, and phosphorylated SHP-2 can associate with the downstream adapter protein Grb2. Finally, deletion of the N terminus but not the kinase-like domain of JAK2 abolishes the association of JAK2 with SHP-2. Taken together, these studies identified novel sequences for SHP-2 and JAK interactions that suggest unique signaling mechanisms mediated by these two molecules.

Animals↗
PubMed1997

[Effect of hyaluronan perfusion through the round window on the function and morphology of the inner ear in guinea pigs].

UNLABELLED: In order to study the effect of the hyaluronan (HA) on the inner ear, twenty-six guinea pigs were divided into experimental and control groups, the experimental group were perfused with 2% HA 0.2 ml through the left round window. Auditory and vestibular function were investigated before and 5, 14, 28 days after perfusion. The threshold of action potential (AP) response to filtered clicks (0.25-10 kHz) were elevated at 5 days and were improved (at 1-4 kHz) at 14 days after perfusion (P < 0.05). At 28 days all AP response thresholds had returned to normal (P > 0.05). The nystagmus duration induced by caloric test (ENG) had no obviously change comparing with that of preoperation (P > 0.05). All guinea pigs were sacrificed 28 days after operation. The histology of inner ear were examined by means of membranous labyrinth mapping and temporal bone section after celloidin embedding. The morphology of Corti's and vestibular organs were not significantly damaged after perfusion. IN CONCLUSION: 1) 2%HA caused reversible and temporary changes in auditory function of inner ear; 2) 2%HA lacked ototoxic adverse effects, whereas exerted considerable osmotic effects and a slow dehydration of inner ears.

Action Potentials↗
PubMed1995

Interleukin-9 induces tyrosine phosphorylation of insulin receptor substrate-1 via JAK tyrosine kinases.

Interleukin (IL)-9 stimulates the proliferation of a variety of hematopoietic lineages through its interaction with a receptor of the cytokine receptor superfamily. In the studies presented here, we have begun to characterize the downstream signaling pathways activated by IL-9. In addition to the activation of JAK1 and JAK3 tyrosine kinases, IL-9, unlike most hematopoietic cytokines but similar to IL-4, induces the tyrosine phosphorylation of a 170-kDa protein that is related to the insulin receptor substrate-1 (IRS-1). We further demonstrate for the first time that IRS-1 is not only associated with JAK1 but also tyrosine phosphorylated and functionally involved in IL-9 signaling in TS1 lymphocytes transfected with the murine IRS-1 cDNA. Cotransfection studies and in vitro experiments directly demonstrate that JAK1, JAK2, or JAK3 is capable of tyrosine phosphorylating IRS-1, suggesting a functional role for these kinases in vivo. Lastly, we demonstrate that IL-9 induces the tyrosine phosphorylation of Stat3 and in this regard differs from IL-4, which triggers tyrosine phosphorylation of Stat6. Taken together, these results strongly suggest that IL-9 and IL-4 utilize common and unique signaling pathways via inducing the similar and distinct tyrosine-phosphorylated proteins.

Animals↗
PubMed1995

Interleukin (IL)-11--mediated signal transduction.

IL-11 is a multifunctional cytokine biologically related to IL-6, leukemia inhibitory factor (LIF), oncostatin M (OSM) and ciliary neurotrophic factor (CNTF). It has been shown that these cytokines can utilize common signal transducer, gp130. We have demonstrated that Jak tyrosine kinases, MAP kinases and pp90rsk are highly activated by IL-11 and related cytokines. In addition, we have identified pp90rsk as one of the H7 sensitive protein kinases critical for primary response gene expression induced by IL-11. Furthermore, activation of 3CH134 (a MAP kinase phosphatase) gene by IL-11 suggested that a MAP kinase phosphatase may be involved in IL-11-mediated signal transduction. Our data also suggested that tyrosine phosphorylation of Stat91 and related transcriptional factors is involved in IL-11 signaling but is not sufficient for the activation of primary response genes such as JunB, tis11, tis8 and MAP kinase phosphatase in mouse preadipocytes. The understanding of signal transduction pathways mediated by IL-11 and related cytokines may help to define the common and unique biological properties of these growth factors.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1995

Tyrosine phosphorylation and activation of JAK family tyrosine kinases by interleukin-9 in MO7E cells.

Interleukin-9 (IL-9) is a T-cell-derived multifunctional cytokine that can stimulate the proliferation of a human megakaryocytic leukemia cell line, MO7E. Previous studies suggested that protein tyrosine phosphorylation may be involved in IL-9 signaling pathways. However, tyrosine kinases activated by IL-9 have not been identified. In this report we show that IL-9 induces tyrosine phosphorylation and activation of the JAK family tyrosine kinases including JAK1, JAK3, and Tyk2. The kinetic studies indicate that tyrosine phosphorylation and activation of JAK kinases induced by IL-9 occurred within 1 minute, peaked by 5 to 10 minutes, and persisted at least for 45 minutes. Furthermore, we show that signal transducers and activators of transcription (Stat) 91 or related protein and an 88-kD Stat 91-associated protein are rapidly tyrosine phosphorylated following IL-9 treatment. Gel shift assays confirm that nuclear extracts from MO7E cells stimulated with IL-9 specifically interact with a DNA element termed gamma activated site. These results suggest that actions of IL-9 may, in part, be mediated through JAK kinase-Stat signaling cascades.

Base Sequence↗
PubMed1994

Molecular basis for type 1 antithrombin deficiency: identification of two novel point mutations and evidence for a de novo splice site mutation.

Inherited type 1 antithrombin (AT) deficiency is characterized by a reduction in both immunologically and functionally detectable protein. The disorder is associated with a high risk of thromboembolic disease. We have investigated the molecular basis of type 1 AT deficiency in three unrelated families. We have used the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis, followed by direct sequencing of the seven exons and the intron-exon junctions of the AT gene. Two novel point mutations were identified. A T to C single-base substitution was found in codon 421 in exon 6 (nucleotide position 13380), leading to an AT 421 isoleucine to threonine substitution. In another kindred, one of three Cs at nucleotide (nt) positions 5448 to 5450 in exon 3A (codon 151 or 152) was deleted, resulting in a frameshift mutation and predicting premature termination of protein translation at codon 251. In a third family, a previously reported G to A substitution, at nt position 9788 in intron 4, 14 bp in front of exon 5, was found. We have demonstrated the creation of a de novo exon 5 splice site by ectopic transcript analysis of lymphocyte mRNA. In all cases, the affected individuals were heterozygous for the mutation and no variant AT protein was detected.

Adolescent↗
PubMed1994

JAK1 kinase forms complexes with interleukin-4 receptor and 4PS/insulin receptor substrate-1-like protein and is activated by interleukin-4 and interleukin-9 in T lymphocytes.

Interleukin (IL)-4 and IL-9 regulate the proliferation of T lymphocytes through interactions with their receptors. Previous studies have shown that unknown tyrosine kinases are involved in the proliferative signaling triggered by IL-4 and IL-9. Here we show that IL-4 and IL-9 induce overlapping (170, 130, and 125 kilodalton (kDa)) and distinct (45 and 88/90 kDa, respectively) protein tyrosine phosphorylation in T lymphocytes. We further identify the 170-kDa tyrosine-phosphorylated protein as 4PS/insulin receptor substrate-1-like (IRS-1L) protein and 130-kDa protein as JAK1 kinase. Furthermore, we demonstrate for the first time that JAK1 forms complexes with the IL-4 receptor and 4PS/IRS-1L protein following ligand-receptor interaction. In addition, we demonstrate that IL-9, but not IL-4, induced tyrosine phosphorylation of Stat 91 transcriptional factor. The overlapping and distinct protein tyrosine phosphorylation and activation of the same JAK1 kinase in T lymphocytes strongly suggests that IL-4 and IL-9 share the common signal transduction pathways and that the specificity for each cytokine could be achieved through the unique tyrosine-phosphorylated proteins triggered by individual cytokines.

Animals↗
PubMed1994

Mitogen-activated protein kinases and ribosomal S6 protein kinases are involved in signaling pathways shared by interleukin-11, interleukin-6, leukemia inhibitory factor, and oncostatin M in mouse 3T3-L1 cells.

The mechanisms of signaling pathways shared by interleukin (IL)-11, IL-6, leukemia inhibitory factor (LIF), and oncostatin M (ONC) remain elusive. We report here that treatment of 3T3-L1 cells with IL-11, IL-6, LIF, and ONC induces overlapping but distinct patterns of tyrosine phosphorylation and activates indistinguishable primary response genes. We further demonstrate for the first time that IL-11, IL-6, LIF, and ONC can trigger the activation of mitogen-activated protein kinases and the 85-92-kDa ribosomal S6 protein kinase (pp90rsk). In addition, our data also show that preincubation of cells with a tyrosine kinase inhibitor herbimycin A, but not with a serine/threonine kinase inhibitor H7, blocks activation of mitogen-activated protein kinases and pp90rsk. Interestingly, H7, but not herbimycin A, inhibits pp90rsk activity in the in vitro kinase assays. These results suggest that pp90rsk is one of the potential candidates for the H7-sensitive protein kinase(s), which is critical for the activation of primary response genes by these cytokines.

3T3 Cells↗
PubMed1994

Identification of a 130-kilodalton tyrosine-phosphorylated protein induced by interleukin-11 as JAK2 tyrosine kinase, which associates with gp130 signal transducer.

Interleukin-11 (IL-11) shares the common signal transducer gp130 with IL-6, leukemia inhibitory factor (LIF), and oncostatin M (OSM) and triggers activation of unknown tyrosine kinases as the early steps of signal transduction pathway. Here we identify a 130-kilodalton tyrosine-phosphorylated protein induced by IL-11 in 3T3-L1 cells as JAK2 tyrosine kinase. We further show that the in vitro kinase activity of JAK2 is greatly enhanced following stimulation with IL-11 in 3T3-L1 cells and TF-1 cells. Furthermore, we demonstrate that JAK2 physically associates with the signal transducer gp130. Similar results were observed following stimulation with IL-6, LIF, and OSM. However, we were unable to show that JAK1 is tyrosine phosphorylated and activated by IL-11 under identical conditions. These results suggest that JAK2 tyrosine kinase is one of the tyrosine kinases involved in signal transduction mediated by IL-11, IL-6, LIF, and OSM.

Antigens, CD↗
PubMed1993

Involvement of IL-6 signal transducer gp130 in IL-11-mediated signal transduction.

IL-11 is a novel cytokine with a variety of biofunctions which overlap with those of IL-6. We have previously identified IL-11 specific binding protein which is distinct from that of IL-6 in a number of cell lines. The similarities in biofunctions and differences in ligand binding proteins between IL-11 and IL-6 prompted us to investigate whether IL-11 shares common signal transduction mechanisms with IL-6. We have examined early signals triggered by IL-11 or IL-6 in a multifactor-dependent human erythroleukemic cell line, TF-1. The results showed that IL-11 and IL-6 can both stimulate cell proliferation, induce similar pattern of protein tyrosine phosphorylation, and activate the same proto-oncogene (junB) expression in TF-1 cells. These findings imply that IL-11 and IL-6 share similar early signaling events with the possibility of using the same signal transducer, gp130. We next tested whether IL-11 induced signaling can be inhibited by anti-gp130 antibodies which blocked IL-6-mediated functions. It was observed that anti-gp130 antibodies abolished cell proliferation, protein tyrosine phosphorylation, and junB gene expression elicited by IL-11 or IL-6 in TF-1 cells. The same antibodies, however, had no effect on granulocyte-macrophage colony stimulating factor or erythropoietin-induced TF-1 cell proliferation. Finally, anti-IL-6R antibody inhibited the ability of IL-6, but not IL-11, to transduce early signals in TF-1 cells. These results demonstrate that IL-11 and IL-6 utilize different ligand binding proteins, but share common signal transducer, gp130, in TF-1 cells.

Animals↗
PubMed1993

In vivo effects of recombinant interleukin-11 on myelopoiesis in mice.

Purified recombinant human interleukin-11 (rhuIL-11) was assessed for its in vivo effects on the proliferation and differentiation of hematopoietic progenitors as well as its capacity to accelerate the recovery of a drug-suppressed hematopoietic system. Dosage and time sequence studies demonstrated that administration of IL-11 to normal mice resulted in increases in absolute numbers of femoral marrow and splenic myeloid (granulocyte-macrophage colony-forming unit [CFU-GM], burst-forming unit-erythroid [BFU-E], CFU-granulocyte, erythroid, macrophage, megakaryocyte) progenitor cells and in stimulation of these progenitors to a higher cell cycling rate. This was associated with increased numbers of circulating neutrophils. Administration of IL-11 to mice pretreated with cyclophosphamide decreased the time required to regain normal levels of neutrophil and platelet counts in peripheral blood. In addition, IL-11 accelerated reconstitution to normal range of myeloid progenitors from bone marrow and spleen of myelosuppressed mice. These data suggest that IL-11 may play an important role in the regulation of hematopoiesis, and the application of this novel cytokine may have clinical therapeutic benefits.

Animals↗
PubMed1993

Protein tyrosine phosphorylation and activation of primary response genes by interleukin 11 in B9-TY1 cells.

Interleukin (IL) 11 is a multifunctional cytokine derived from bone marrow stromal cells. To understand the mechanisms by which IL-11 exerts its pleiotropic actions, we have analyzed IL-11-mediated signal transduction pathways in IL-11-dependent B9-TY1, which is a subclone of an IL-6-dependent B-cell hybridoma, B9. IL-11 stimulation of B9-TY1 cells resulted in tyrosine phosphorylation of a 97/95 kilodalton cellular protein in a dose-dependent manner, and this effect was inhibited by tyrosine kinase inhibitors genistein and herbimycin A, but not by a serine/threonine kinase inhibitor, H7. We next examined the early nuclear events in the IL-11-triggered intracellular signaling cascade. The data showed that tis11, tis21, and junB early response genes were rapidly activated following IL-11 treatment. The kinetic studies indicated that activation of tis11 and junB genes peaked at 30-60 min and then declined slowly afterward. The tis21 gene was constitutively expressed, and the level of tis21 mRNA was significantly increased and maintained at the elevated level following IL-11 stimulation. Inhibitor studies with genistein, herbimycin A, and H7 revealed that tyrosine kinases and H7-sensitive serine/threonine kinases are required for the IL-11-mediated activation of tis11, tis21, and junB genes. Using a variety of known protein kinase inhibitors or activators, we have demonstrated that H7-sensitive protein kinases activated by IL-11 are distinct from those of well-characterized protein kinase-second messenger systems.(ABSTRACT TRUNCATED AT 250 WORDS)

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1992

Characterization of interleukin-11 receptor and protein tyrosine phosphorylation induced by interleukin-11 in mouse 3T3-L1 cells.

In this study, we have characterized the biochemical nature of interleukin (IL)-11 receptors (IL-11R) and determined the possible signal transduction pathways mediated by IL-11 in 3T3-L1 mouse preadipocytes. The results show that IL-11 strongly inhibited lipoprotein lipase activity and adipogenesis in 3T3-L1 cells, and the suppression of lipoprotein lipase activity by IL-11 was controlled at the post-transcriptional level. The ability of IL-11 to inhibit lipoprotein lipase activity and adipogenesis therefore reflected the expression of functional IL-11R on the cell surface. Scatchard plot analysis according to specific binding data revealed the existence of a single class of high affinity IL-11R with a Kd of 3.49 x 10(-10) M and a receptor density of 5140 sites/cell on 3T3-L1 cells. Affinity cross-linking studies with 125I-IL-11 indicated that IL-11R consists of a single polypeptide chain of 151 kDa in size. Furthermore, we have studied the role of protein tyrosine phosphorylation in the IL-11R-linked signal transduction pathways. The results show that IL-11R ligation rapidly and transiently stimulated tyrosine phosphorylation of 152-, 94-, 47-, and 44-kDa proteins. This effect is specific for IL-11 since neutralizing antibody to IL-11 abrogated IL-11-induced tyrosine phosphorylation, and other cytokines such as IL-6 and IL-1 alpha did not change the tyrosine phosphorylation pattern in 3T3-L1 cells. These results suggest that IL-11R is closely linked to a functional protein-tyrosine kinase pathway, and tyrosine phosphorylation may be a key step in the initiation of the IL-11R-mediated transmembrane signaling.

3T3 Cells↗
PubMed1992

Interleukin-11 and its receptor.

Interleukin (IL)-11 is a bone marrow fibroblast derived cytokine with a wide spectrum of activities in different biological systems. It has been shown that IL-11 supports the growth of certain types of plasmacytoma and hybridoma cells, enhances antigen-specific antibody responses, synergizes with IL-3 in supporting megakaryocyte colony formation, acts synergistically with IL-3 in shortening the G0 period of early progenitors, induces the synthesis of acute phase proteins, and inhibits lipoprotein lipase activity and adipocyte differentiation. The human IL-11 gene, which is localized at 19q13.3-13.4, consists of five exons and four introns. Initial biochemical characterization has identified a 151 kDa protein as the potential IL-11 binding subunit of the receptor complex. Because of the overlapping biological activities between IL-6 and IL-11, we compared the signal transduction pathways mediated by IL-6 or IL-11 in cell lines responsive to both cytokines. Results from protein tyrosine phosphorylation and immediate response gene expression suggest that there are convergent and divergent points along the signal transduction pathways utilized by IL-6 or IL-11. The IL-6 signal transducer, gp130, appears to be involved in the IL-11 mediated signaling. Other cytokines such as leukemia inhibitory factor, oncostatin M and ciliary neurotrophic factor have also been shown to utilize gp130 as a signal transducer. The significance of growth factor sharing common biological activities and signaling pathways will be discussed.

Animals↗