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Biomedical subjects

T Kitamura

Publications and source records attributed to T Kitamura.

At least 181 records · Page 10Linked to original sources
PubMed2000

Magnetic stimulation of the sacral roots for the treatment of stress incontinence: an investigational study and placebo controlled trial.

PURPOSE: We designed an investigational study and placebo controlled trial to evaluate the potential efficacy of magnetic stimulation of the sacral roots for the treatment of stress incontinence. MATERIALS AND METHODS: A total of 75 patients with stress incontinence were studied. A 15 Hz. repetitive magnetic stimulation of the sacral roots with 50% intensity output and duration of 5 seconds per minute was applied for 30 minutes. Urodynamic investigations under magnetic stimulation were performed in 13 patients to evaluate acute effects to lower urinary tract function. There were 62 women (mean age 58 years) enrolled in a placebo controlled study to investigate the short-term efficacy of magnetic stimulation. The number of leaks for 3 days, amount of urine loss on a pad test and quality of life score were evaluated before and 1 week after stimulation. RESULTS: The urodynamic investigations revealed an apparent elevation of urethral closure pressure induced by stimulation (mean 8.2 +/- 3.0 cm H2O, p = 0.0000004) and a significant increase in bladder capacity after stimulation (mean 40.0 +/- 51.0 ml., p = 0.0152). In the placebo controlled study the number of leaks and amount of urine loss on a pad test significantly decreased more in the active than in the sham stimulation group (p = 0.0023 and 0.0377, respectively). The quality of life score significantly improved in the active stimulation group (p = 0.0006) in contrast to no significant improvement in the sham stimulation group. The improvement rate in the active stimulation group was 74%, which was significantly higher than the 32% in the sham stimulation group (p = 0.0009). No adverse effects were noted in any patients. CONCLUSIONS: These results suggest that magnetic stimulation of the sacral roots may be useful for the treatment of stress incontinence. Further studies are needed to evaluate the long-term efficacy of this potential treatment.

Adult↗
PubMed2000

Higher prevalence and viral load of TT virus in saliva than in the corresponding serum: another possible transmission route and replication site of TT virus.

Although TT virus (TTV) is transmissible by blood or blood products, many patients with no history of transfusion of blood and blood products have been shown to be infected, suggesting other possible routes of transmission. To investigate the transmission routes and replication sites of TTV, 85 paired saliva and serum samples were studied by semi-nested polymerase chain reaction. The prevalence of TTV DNA was 38% (32/85 samples) and 21% (18/85) in saliva and serum, respectively. Fifteen patients had TTV DNA both in saliva and serum. Six out of fifteen patients had significantly higher viral titers in saliva than in serum, but none had higher titer in serum than in saliva. When the 222 base-pair nucleotide sequences of PCR products amplified from the samples were analyzed, 12 patients had the same genotype/subtype in saliva and serum and exhibited high homology (96-100%). The other 3 had different genotypes/subtypes in saliva and serum, and the homology was 61.9-87.2%. Mixed infection was observed both in saliva and serum. Further studies are required to determine if a subgroup of TTV has tropism to saliva. The high prevalence and viral load of TTV in saliva suggest that salivary fluid may be a possible route of transmission of TTV and that TTV might replicate not only in liver tissue but also in other tissues such as oropharyngeal tissues and/or salivary glands.

Aged↗
PubMed1999

A novel glycosyltransferase with a polyglutamine repeat; a new candidate for GD1alpha synthase (ST6GalNAc V)(1).

The fifth type GalNAcalpha2,6-sialyltransferase (mST6GalNAc V) was cloned from a mouse brain cDNA library. mST6GalNAc V exhibited type II transmembrane topology containing a polyglutamine repeat, which showed 42.6% and 44.8% identity to mouse ST6GalNAc III and IV, respectively. Northern blot analysis revealed that the mST6GalNAc V gene was specifically expressed in forebrain and cerebellum. mST6GalNAc V exhibited GD1alpha synthetic activity from GM1b the same as mST6GalNAc III and IV. The activity ratio of GM1b toward fetuin and the expression pattern were completely different among the three ST6GalNAcs. Interestingly, the polyglutamine repeat number was different from that of inbred mice. We report the first glycosyltransferase with a polymorphic polyglutamine repeat.

Amino Acid Sequence↗
PubMed1999

Regulation of nuclear translocation of forkhead transcription factor AFX by protein kinase B.

The regulation of intracellular localization of AFX, a human Forkhead transcription factor, was studied. AFX was recovered as a phosphoprotein from transfected COS-7 cells growing in the presence of FBS, and the phosphorylation was eliminated by wortmannin, a potent inhibitor of phosphatidylinositol (PI) 3-kinase. AFX was phosphorylated in vitro by protein kinase B (PKB), a downstream target of PI 3-kinase, but a mutant protein in which three putative phosphorylation sites of PKB had been replaced by Ala was not recognized by PKB. In Chinese hamster ovary cells (CHO-K1) cultured with serum, the AFX protein fused with green fluorescence protein (AFX-GFP) is localized mainly in the cytoplasm, and wortmannin induced transient nuclear translocation of the fusion protein. The AFX-GFP mutant in which all three phosphorylation sites had been replaced by Ala was detected exclusively in the cell nucleus. AFX-GFP was in the nucleus when the cells were infected with an adenovirus vector encoding a dominant-negative form of either PI 3-kinase or PKB, whereas the fusion protein stayed in the cytoplasm when the cells expressed constitutively active PKB. In CHO-K1 cells expressing AFX-GFP, DNA fragmentation was induced by the stable PI 3-kinase inhibitor LY294002, and the expression of the active form of PKB suppressed this DNA fragmentation. The phosphorylation site mutant of AFX-GFP enhanced DNA fragmentation irrespective of the presence and absence of PI 3-kinase inhibitor. These results indicate that the nuclear translocation of AFX is negatively regulated through its phosphorylation by PKB.

Animals↗
PubMed1999

Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor.

Idiopathic pulmonary alveolar proteinosis (I-PAP) is a rare disease of unknown etiology in which the alveoli fill with lipoproteinaceous material. We report here that I-PAP is an autoimmune disease with neutralizing antibody of immunoglobulin G isotype against granulocyte/macrophage colony-stimulating factor (GM-CSF). The antibody was found to be present in all specimens of bronchoalveolar lavage fluid obtained from 11 I-PAP patients but not in samples from 2 secondary PAP patients, 53 normal subjects, and 14 patients with other lung diseases. It specifically bound GM-CSF and neutralized bioactivity of the cytokine in vitro. The antibody was also found in sera from all I-PAP patients examined but not in sera from a secondary PAP patient or normal subjects, indicating that it exists systemically in I-PAP patients. As lack of GM-CSF signaling causes PAP in congenital cases and PAP-like disease in murine models, our findings strongly suggest that neutralization of GM-CSF bioactivity by the antibody causes dysfunction of alveolar macrophages, which results in reduced surfactant clearance.

Autoantibodies↗
PubMed1999

STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells.

Signal transducers and activators of transcription (STATs) play key roles in growth factor-mediated intracellular signal transduction. In the present study using a constitutively active STAT5 mutant, we show that STAT5 has pleiotropic functions regulating cell proliferation, differentiation and apoptosis in an IL-3-dependent Ba/F3 cell line. The mutant STAT5 possessed constitutive tyrosine phosphorylation and DNA binding activity, induced expression of bcl-xL and pim-1 in the absence of IL-3 in Ba/F3 cells, and rendered Ba/F3 cells factor-independent. Unexpectedly, IL-3 treatment of the factor-independent Ba/F3 cells expressing the constitutively active STAT5 resulted in apoptosis within 24 h, or differentiation followed by cell death. In these cells, mRNA expression of growth inhibitory genes downstream of STAT5 such as CIS, JAB/SOCS-1/SSI-1, and p21(WAF1/Cip1) was highly induced, correlating with prolonged hyper-phosphorylation of the mutant STAT5 after IL-3 stimulation. Of the STAT5-regulated genes, we found that constitutive expression of JAB/SOCS-1/SSI-1 was sufficient to induce apoptosis of Ba/F3 cells, while p21(WAF1/Cip1) could induce differentiation of these cells. In contrast, constitutive expression of pim-1 was sufficient to induce IL-3-independent growth of Ba/F3 cells. These findings suggest that a single transcription factor regulates cell fate by varying the intensity and duration of the expression of a set of target genes.

Animals↗
PubMed1999

Dominant negative forms of Akt (protein kinase B) and atypical protein kinase Clambda do not prevent insulin inhibition of phosphoenolpyruvate carboxykinase gene transcription.

Transcriptional regulation of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme in hepatic gluconeogenesis, by insulin was investigated with the use of adenovirus vectors encoding various mutant signaling proteins. Insulin inhibited transcription induced by dexamethasone and cAMP of a chloramphenicol acetyltransferase (CAT) reporter gene fused with the PEPCK promoter sequence in HL1C cells stably transfected with this construct. A dominant negative mutant of phosphoinositide (PI) 3-kinase blocked insulin inhibition of transcription of the PEPCK-CAT fusion gene, whereas a constitutively active mutant of PI 3-kinase mimicked the effect of insulin. Although a constitutively active mutant of Akt (protein kinase B) inhibited PEPCK-CAT gene transcription induced by dexamethasone and cAMP, a mutant Akt (Akt-AA) in which the phosphorylation sites targeted by insulin are replaced by alanine did not affect the ability of insulin to inhibit transcription of the fusion gene. Akt-AA almost completely inhibited insulin-induced activation of both endogenous and recombinant Akt in HL1C cells. Furthermore, neither a kinase-defective mutant protein kinase Clambda (PKClambda), which blocked insulin-induced activation of endogenous PKClambda, nor a dominant negative mutant of the small GTPase Rac prevented inhibition of PEPCK-CAT gene transcription by insulin. These data suggest that phosphoinositide 3-kinase is important for insulin-induced inhibition of PEPCK gene transcription and that a downstream effector of phosphoinositide 3-kinase distinct from Akt, PKClambda, and Rac may exist for mediating the effect of insulin.

Cell Line↗
PubMed1999

Requirement for Akt (protein kinase B) in insulin-induced activation of glycogen synthase and phosphorylation of 4E-BP1 (PHAS-1).

The roles of Akt (protein kinase B) and the atypical lambda isoform of protein kinase C (PKClambda), both of which act downstream of phosphoinositide 3-kinase, in the activation of glycogen synthase and phosphorylation of 4E-BP1 (PHAS-1) in response to insulin were investigated. A mutant Akt (Akt-AA) in which the phosphorylation sites targeted by growth factors are replaced by alanine was shown to inhibit insulin-induced activation of both Akt and glycogen synthase in L6 myotubes. Expression of a mutant Akt in which Lys179 in the kinase domain was replaced by aspartate also inhibited insulin-induced activation of glycogen synthase but had no effect on insulin activation of endogenous Akt. A kinase-defective mutant of PKClambda (lambdaDeltaNKD), which prevents insulin-induced activation of PKClambda, did not affect the activation of glycogen synthase by insulin. Insulin-induced phosphorylation of 4E-BP1 was inhibited by Akt-AA in Chinese hamster ovary cells. However, lambdaDeltaNKD had no effect on 4E-BP1 phosphorylation induced by insulin. These data suggest that Akt, but not PKClambda, is required for insulin activation of glycogen synthase and for insulin-induced phosphorylation of 4E-BP1.

Amino Acid Sequence↗
PubMed1999

Transplacental administration of diethylstilbestrol (DES) causes lesions in female reproductive organs of Donryu rats, including endometrial neoplasia.

The effects of transplacental administration of diethylstilbestrol (DES) on female reproductive organs were investigated using Donryu rats. The animals were given subcutaneous injections of DES dissolved in olive oil at doses of 0.01 or 0.1 mg/kg on days 17 and 19 of gestation. In female offspring, clinical signs, body weights and estrous cycles were continuously assessed until all survivors were killed at month 18. A low mean litter size and shortening of period of pregnancy were recognized in the 0.1 mg/kg group. Disorder and/or suspension of the estrous cycle (so called persistent estrus) also appeared very early in the 0.1 mg/kg group. Macroscopically, the incidences of hypoplasia of the oviduct, cystic dilatation of the uterus and small size of the uterine cervix were higher in the 0.1 mg/kg group than those in the control group. Histologically, in the ovary, the incidence and degree of atrophy were increased in both 0.01 and 0.1 mg/kg groups. In the uterus, total incidences of endometrial hyperplasias were about the same in all groups. However, endometrial adenocarcinomas were dose-dependently increased in the treated groups, the incidence in the 0.1 mg/kg group being significant, compared to that in the control. In the vagina, mucification was more prominent in the treated animals, especially at the higher dose, but no tumors were observed. The present results indicate that prenatal exposure to DES can produce uterine adenocarcinomas in rats, as reported earlier for mice, although its carcinogenic activity is not so strong. Increase of endometrial adenocarcinoma incidence might depend on hormonal imbalance resulting from the ovarian atrophy due to transplacental treatment of DES.

Adenocarcinoma↗
PubMed1999

Structure and regulation of the human NeuroD (BETA2/BHF1) gene.

In this study, we isolated and characterized the human NeuroD (BETA2/BHF1) gene. This gene was found to consist of two exons and one intron. The promoter regions were well-conserved compared with the mouse NeuroD gene. Two transcription start points (TSPs) were determined by the oligo-capping method. One TATA box was located at -31 bp from the lower TSP. The results of a transient transfection assay using the human neuroblastoma cell line IMR-32 and hamster insulin tumor cell line HIT-T15 suggested that there are at least three positive regulatory regions in the promoter. In these regions, four E boxes (CANNTG), named the E1 to E4 boxes, and two GC boxes were present. Cotransfection of the NeuroD expression vector into IMR-32 cells enhanced the NeuroD promoter activity by about 4-fold. A deletion and mutation analysis revealed that the E1 and E4 boxes, especially the E1 box, are associated with autoactivation and that E2 and E3 boxes are not associated with autoactivation. As mutation analysis of E3 box showed a decrease in the enhancer activity to the basal level, it showed that the E3 box is important to activate the NeuroD transcription. These results raised the possibility that the NeuroD gene expression is positively regulated through the E box sequence, not only by NeuroD itself but also by another E box binding protein.

Animals↗
PubMed1999

Establishment of a new system for determination of coreceptor usages of HIV based on the human glioma NP-2 cell line.

CD4 and one of the G-protein-coupled receptors (GPCRs) on the cell surface function as a receptor and a coreceptor, respectively, in infection of cells with human and simian immunodeficiency viruses (HIV/SIV). To determine which GPCRs can be coreceptors for HIV (HIV-1 and HIV-2) or SIV infection, several cell lines, including human osteosarcoma HOS-T4 cells and human glioma U87/CD4 cells, have been used. However, these cells often show susceptibilities to some HIV or SIV strains before transduction of GPCRs. The results of this study showed that a CD4-transduced human glioma cell line, NP-2/CD4, a human erythroleukemia cell line, K562/CD4, and a human ovarian cancer cell line, TYK/CD4, were completely resistant to the HIV-1 and HIV-2 strains tested. After transduction of several GPCRs into NP-2/CD4, K562/CD4, or TYK/CD4 cells, NP-2/CD4 cells but not K562/CD4 or TYK/CD4 cells mostly showed expected susceptibilities to several HIV strains. Therefore, an NP-2 cell system would be useful to determine the coreceptor usage of HIV isolates, to find a new coreceptor for HIV/SIV, and to analyze the early stages of HIV/SIV infection.

Base Sequence↗
PubMed1999

Butyrolactone I induces cyclin B1 and causes G2/M arrest and skipping of mitosis in human prostate cell lines.

Several naturally occurring cyclin-dependent kinase (CDK) inhibitors have been isolated from different lower organisms. In this report, we examined the effect of one of the CDK inhibitors, butyrolactone I (BL), on the expression of cyclins D2, A and B1 in three human prostatic cancer cell lines (DU145, PC-3, LNCaP) using two colored flow cytometric analysis. The percentage of DU145 cells in the 4C phase of the cell cycle were increased significantly at both 70 microM and 100 microM BL. Furthermore, an additional 8C peak was observed which had double the DNA content of the 4C phase at these concentrations of BL. The appearance of the 8C peak increased gradually and was more evident in DU145 and PC-3 than LNCaP. Cells in the 8C peak had either two nuclei or abnormal nuclei as observed by Papanicolaou stain. BL also increased the amount of cyclin B1 positive cells in the 4C phase. This increase was apparent on day 1 and returned to normal by day 3. Since BL selectively inhibits cyclin-dependent kinase, cyclin B1 might accumulate without being degraded. Other cyclins were not significantly changed by BL. The data demonstrate that BL inhibited Cdc2 of unsynchronized cultured prostate cancer cells, and interrupted the cell cycle progression toward cell division. The BL inhibition of Cdc2 led to the accumulation of cells in the 4C phase without mitosis resulting in an accumulation of cyclin B1. The appearance of cells in the 8C phase may be due to the progression of cells in the 4C phase through the cell cycle skipping mitosis. Cyclin B1 decreased in correlation with the progression through a new cell cycle. These results suggest that BL does not cause a complete arrest of the cell cycle in G2/M but that BL occasionally allows for the skipping of mitosis and subsequent progression through the cell cycle to occur.

4-Butyrolactone↗
PubMed1999

Signal transducer and activator of transcription (STAT)5 activation by BCR/ABL is dependent on intact Src homology (SH)3 and SH2 domains of BCR/ABL and is required for leukemogenesis.

Signal transducer and activator of transcription (STAT)5 is constitutively activated in BCR/ ABL-expressing cells, but the mechanisms and functional consequences of such activation are unknown. We show here that BCR/ABL induces phosphorylation and activation of STAT5 by a mechanism that requires the BCR/ABL Src homology (SH)2 domain and the proline-rich binding site of the SH3 domain. Upon expression in 32Dcl3 growth factor-dependent myeloid precursor cells, STAT5 activation-deficient BCR/ABL SH3+SH2 domain mutants functioned as tyrosine kinase and activated Ras, but failed to protect from apoptosis induced by withdrawal of interleukin 3 and/or serum and did not induce leukemia in severe combined immunodeficiency mice. In complementation assays, expression of a dominant-active STAT5B mutant (STAT5B-DAM), but not wild-type STAT5B (STAT5B-WT), in 32Dcl3 cells transfected with STAT5 activation-deficient BCR/ABL SH3+SH2 mutants restored protection from apoptosis, stimulated growth factor-independent cell cycle progression, and rescued the leukemogenic potential in mice. Moreover, expression of a dominant-negative STAT5B mutant (STAT5B-DNM) in 32Dcl3 cells transfected with wild-type BCR/ABL inhibited apoptosis resistance, growth factor-independent proliferation, and the leukemogenic potential of these cells. In retrovirally infected mouse bone marrow cells, expression of STAT5B-DNM inhibited BCR/ABL-dependent transformation. Moreover, STAT5B-DAM, but not STAT5B-WT, markedly enhanced the ability of STAT5 activation-defective BCR/ABL SH3+SH2 mutants to induce growth factor-independent colony formation of primary mouse bone marrow progenitor cells. However, STAT5B-DAM did not rescue the growth factor-independent colony formation of kinase-deficient K1172R BCR/ABL or the triple mutant Y177F+R522L+ Y793F BCR/ABL, both of which also fail to activate STAT5. Together, these data demonstrate that STAT5 activation by BCR/ABL is dependent on signaling from more than one domain and document the important role of STAT5-regulated pathways in BCR/ABL leukemogenesis.

Animals↗
PubMed1999

Correlation between proliferation, apoptosis, and angiogenesis in prostate carcinoma and their relation to androgen ablation.

BACKGROUND: Proliferation, apoptosis, and angiogenesis are essential for carcinogenesis. Little is known regarding the relation between proliferation, apoptosis, and angiogenesis in untreated prostate carcinoma as well as alterations associated with androgen ablation. METHODS: Eighty patients who underwent radical prostatectomy for clinically localized prostate carcinoma were recruited for the study. The study population included 2 groups: 35 patients receiving 3-month neoadjuvant hormonal treatment using a combination of luteinizing hormone-releasing hormone analogue and the antiandrogen flutamide (NHT group) and 45 patients without prior treatment (non-NHT group). The authors measured the Ki-67 labeling index (Ki-67 LI) by MIB-1 immunohistochemistry, the apoptotic index (AI) by the terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling technique, and intratumoral microvessel density (IMVD) by CD31 immunohistochemistry on serial sections of formalin fixed, paraffin embedded tissues. Correlations among these parameters were examined in both groups. RESULTS: A significant decrease in the Ki-67 LI coupled with a significant increase in AI was found in the NHT group compared with the non-NHT group, whereas IMVDs in both groups were not significantly different. AI was related to IMVD inversely in the non-NHT group (correlation coefficient [r] = -0.327; P = 0.03); in contrast, AI was related to IMVD positively in the non-NHT group (r = 0.579; P < 0.001). The Ki-67 LI was related to AI significantly in the non-NHT group but not in the NHT group. There was no correlation between Ki-67 LI and IMVD in either group. CONCLUSIONS: Correlations between proliferation, apoptosis, and angiogenesis in prostate carcinoma are altered significantly in association with androgen ablation. The results indicate that spontaneous apoptosis is suppressed by neovascularization, whereas hormone-induced apoptosis is enhanced in hypervascular tumors.

Adenocarcinoma↗
PubMed1999

Identification and analysis of the promoter region of the human NeuroD-related factor (NDRF)1.

We isolated and characterized the human NeuroD-related factor (NDRF)/NeuroD2/KW8 gene. The NDRF gene consisted of two exons and one intron. NDRF had one transcriptional starting point, and in its 5'-flanking region, no TATA box was detected, but 16 E boxes (CANNTG) were present. RNA blotting analysis revealed that HIT-T15 and D283 cells expressed a 3.3 kb band of the NDRF transcript. Promoter analysis by luciferase assay demonstrated that luciferase activity changed between -120 and -195, and between -451 and -564, both regions wherein a single E box existed. Radiation hybrid mapping showed that NDRF linked the marker SHGC-36242 with a LOD score of 8.53 and was located on 17q12-22.

Animals↗
PubMed1999

Tyrosine phosphorylation of p62(Dok) induced by cell adhesion and insulin: possible role in cell migration.

Dok, a 62-kDa Ras GTPase-activating protein (rasGAP)-associated phosphotyrosyl protein, is thought to act as a multiple docking protein downstream of receptor or non-receptor tyrosine kinases. Cell adhesion to extracellular matrix proteins induced marked tyrosine phosphorylation of Dok. This adhesion-dependent phosphorylation of Dok was mediated, at least in part, by Src family tyrosine kinases. The maximal insulin-induced tyrosine phosphorylation of Dok required a Src family kinase. A mutant Dok (DokDeltaPH) that lacked its pleckstrin homology domain failed to undergo tyrosine phosphorylation in response to cell adhesion or insulin. Furthermore, unlike the wild-type protein, DokDeltaPH did not localize to subcellular membrane components. Insulin promoted the association of tyrosine-phosphorylated Dok with the adapter protein NCK and rasGAP. In contrast, a mutant Dok (DokY361F), in which Tyr361 was replaced by phenylalanine, failed to bind NCK but partially retained the ability to bind rasGAP in response to insulin. Overexpression of wild-type Dok, but not that of DokDeltaPH or DokY361F, enhanced the cell migratory response to insulin without affecting insulin activation of mitogen-activated protein kinase. These results identify Dok as a signal transducer that potentially links, through its interaction with NCK or rasGAP, cell adhesion and insulin receptors to the machinery that controls cell motility.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Transcriptional regulation of the cyclin D1 promoter by STAT5: its involvement in cytokine-dependent growth of hematopoietic cells.

STAT5 is a member of a family of transcription factors that participate in the signal transduction pathways of many hormones and cytokines. Although STAT5 is suggested to play a crucial role in the biological effects of cytokines, its downstream target(s) associated with cell growth control is largely unknown. In a human interleukin-3 (IL-3)-dependent cell line F-36P-mpl, the induced expression of dominant-negative (dn)-STAT5 and of dn-ras led to inhibition of IL-3-dependent cell growth, accompanying the reduced expression of cyclin D1 mRNA. Also, both constitutively active forms of STAT5A (1*6-STAT5A) and ras (H-rasG12V) enabled F-36P-mpl cells to proliferate without added growth factors. In NIH 3T3 cells, 1*6-STAT5A and H-rasG12V individually and cooperatively transactivated the cyclin D1 promoter in luciferase assays. Both dn-STAT5 and dn-ras suppressed IL-3-induced cyclin D1 promoter activities in F-36P-mpl cells. Using a series of mutant cyclin D1 promoters, 1*6-STAT5A was found to transactivate the cyclin D1 promoter through the potential STAT-binding sequence at -481 bp. In electrophoretic mobility shift assays, STAT5 bound to the element in response to IL-3. Furthermore, the inhibitory effect of dn-STAT5 on IL-3-dependent growth was restored by expression of cyclin D1. Thus STAT5, in addition to ras signaling, appears to mediate transcriptional regulation of cyclin D1, thereby contributing to cytokine-dependent growth of hematopoietic cells.

Cell Cycle↗