17 results on '"Miyazono K"'
Search Results
2. Genome-wide mechanisms of Smad binding.
- Author
-
Morikawa, M, Koinuma, D, Miyazono, K, and Heldin, C-H
- Subjects
- *
GENOMICS , *SMAD proteins , *TRANSFORMING growth factors-beta , *CELLULAR signal transduction , *BIOMARKERS , *CANCER diagnosis , *CANCER treatment - Abstract
A dual role of transforming growth factor β (TGF-β), to both suppress and promote tumor progression and metastasis, has been well established, but its molecular basis has remained elusive. In this review, we focus on Smad proteins, which are central mediators of the signal transduction of TGF-β family members. We describe current knowledge of cell-type-specific binding patterns of Smad proteins and mechanisms of transcriptional regulation, obtained from recent studies on genome-wide binding sites of Smad molecules. We also discuss potential application of the genome-wide analyses for cancer research, which will allow clarification of the complex mechanisms occurring during cancer progression, and the identification of potential biomarkers for future cancer diagnosis, prognosis and therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
3. MicroRNA regulons in tumor microenvironment.
- Author
-
Suzuki, H I, Katsura, A, Matsuyama, H, and Miyazono, K
- Subjects
- *
CANCER cells , *CANCER invasiveness , *MICRORNA , *REGULONS , *BIOLOGICAL crosstalk , *IMMUNOMODULATORS , *TUMOR suppressor genes - Abstract
Cancer initiation and progression are defined by the behavior of cancer cells per se and the development of tumor tissues, both of which are modulated by crosstalk between cancer cells and the surrounding microenvironment. Advances in cancer research have highlighted the significance of constant evolution of the tumor microenvironment, leading to tumor formation, metastasis and refractoriness to therapy. MicroRNAs (miRNAs) are small non-coding RNAs that function as major players of posttranscriptional gene regulation in diverse biological processes. They function as both tumor suppressors and promoters in many aspects of the autonomous behavior of cancer cells. Theoretically, dysfunction in the gene regulatory networks of cancer cells is one of the major driving forces for alterations of ostensibly normal surrounding cells. In this context, the core targets of miRNAs, termed miRNA regulons, are currently being expanded to include various modulators of the tumor microenvironment. Recent advances have highlighted two important roles played by miRNAs in the evolution of tumor microenvironments: miRNAs in tumor cells transform the microenvironment via non-cell-autonomous mechanisms, and miRNAs in neighboring cells stabilize cancer hallmark traits. These observations epitomize the distal and proximal functions of miRNAs in tumor microenvironments, respectively. Such regulation by miRNAs affects tumor angiogenesis, immune invasion and tumor-stromal interactions. This review summarizes recent findings on the mechanisms of miRNA-mediated regulation of tumor microenvironments, with a perspective on the design of therapeutic interventions. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
4. EVI1 oncogene promotes KRAS pathway through suppression of microRNA-96 in pancreatic carcinogenesis.
- Author
-
Tanaka, M, Suzuki, H I, Shibahara, J, Kunita, A, Isagawa, T, Yoshimi, A, Kurokawa, M, Miyazono, K, Aburatani, H, Ishikawa, S, and Fukayama, M
- Subjects
- *
PANCREATIC cancer treatment , *ONCOGENES , *PANCREATIC cancer genetics , *CANCER invasiveness , *MICRORNA genetics , *CARCINOGENESIS , *CANCER cell growth - Abstract
Despite frequent KRAS mutation, the early molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) development have not been fully elucidated. By tracking a potential regulator of another feature of PDAC precursors, acquisition of foregut or gastric epithelial gene signature, we herein report that aberrant overexpression of ecotropic viral integration site 1 (EVI1) oncoprotein, which is usually absent in normal pancreatic duct, is a widespread marker across the full spectrum of human PDAC precursors and PDAC. In pancreatic cancer cells, EVI1 depletion caused remarkable inhibition of cell growth and migration, indicating its oncogenic roles. Importantly, we found that EVI1 upregulated KRAS expression through suppression of a potent KRAS suppressor, miR-96, in pancreatic cancer cells. Collectively, the present findings suggest that EVI1 overexpression and KRAS mutation converge on activation of the KRAS pathway in early phases of pancreatic carcinogenesis and propose EVI1 and/or miR-96 as early markers and therapeutic targets in this dismal disease. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
5. Computational dissection of distinct microRNA activity signatures associated with peripheral T cell lymphoma subtypes.
- Author
-
Suzuki, H I, Matsuyama, H, Noguchi, M, Yao, T, Komatsu, N, Mano, H, Sugimoto, K, and Miyazono, K
- Subjects
- *
T cells , *LYMPHOCYTES - Abstract
A letter to the editor is presented in response to the article related to microRNA activity signatures associated with peripheral T cell lymphoma subtypes in the May 10, 2013 issue.
- Published
- 2013
- Full Text
- View/download PDF
6. Specific interactions between Smad proteins and AP-1 components determine TGFβ-induced breast cancer cell invasion.
- Author
-
Sundqvist, A, Zieba, A, Vasilaki, E, Herrera Hidalgo, C, Söderberg, O, Koinuma, D, Miyazono, K, Heldin, C-H, Landegren, U, ten Dijke, P, and van Dam, H
- Subjects
- *
SMAD proteins , *AP-1 transcription factor , *TRANSFORMING growth factors-beta , *BREAST cancer , *CANCER invasiveness , *CELLULAR signal transduction , *CANCER cell proliferation - Abstract
Deregulation of the transforming growth factor β (TGFβ) signal transduction cascade is functionally linked to cancer. In early phases, TGFβ acts as a tumor suppressor by inhibiting tumor cell proliferation, whereas in late phases, it can act as a tumor promoter by stimulating tumor cell invasion and metastasis. Smad transcriptional effectors mediate TGFβ responses, but relatively little is known about the Smad-containing complexes that are important for epithelial-mesenchymal transition and invasion. In this study, we have tested the hypothesis that specific members of the AP-1 transcription factor family determine TGFβ signaling specificity in breast cancer cell invasion. Using a 3D model of collagen-embedded spheroids of MCF10A-MII premalignant human breast cancer cells, we identified the AP-1 transcription factor components c-Jun, JunB, c-Fos and Fra1 as essential factors for TGFβ-induced invasion and found that various mesenchymal and invasion-associated TGFβ-induced genes are co-regulated by these proteins. In situ proximity ligation assays showed that TGFβ signaling not only induces complexes between Smad3 and Smad4 in the nucleus but also complexes between Smad2/3 and Fra1, whereas complexes between Smad3, c-Jun and JunB could already be detected before TGFβ stimulation. Finally, chromatin immunoprecipitations showed that c-Jun, JunB and Fra1, but not c-Fos, are required for TGFβ-induced binding of Smad2/3 to the mmp-10 and pai-1 promoters. Together these results suggest that in particular formation of Smad2/3-Fra1 complexes may reflect activation of the Smad/AP-1-dependent TGFβ-induced invasion program. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
7. Epithelial to Mesenchymal Transition in Murine Tracheal Allotransplantation: An Immunohistochemical Observation.
- Author
-
Konoeda, C., Koinuma, D., Morishita, Y., Sano, A., Nagayama, K., Motomura, N., Kakimi, K., Miyazono, K., Nakajima, J., Nicolls, M.R., and Murakawa, T.
- Subjects
- *
TRACHEAL surgery , *EPITHELIAL cells , *TRANSPLANTATION of organs, tissues, etc. , *BRONCHIOLITIS , *LUNG transplantation , *SMOOTH muscle , *IMMUNOHISTOCHEMISTRY , *AIRWAY (Anatomy) - Abstract
Abstract: Background: Aberrant epithelial repair is a crucial event in the airway remodeling that characterizes obliterative bronchiolitis (OB) in transplanted lungs. Recent data from experiments using epithelial cell lines and human airway tissues from lung transplant recipients suggest that epithelial to mesenchymal transition (EMT) plays an important role in OB. The aim of this study was to clarify whether EMT is involved in airway remodeling in an animal model. Methods: We performed orthotopic tracheal transplantation from BALB/c to C57BL/6 mice with from BALC/c to BALB/c mouse grafts as controls. Five allogeneic and 3 syngeneic recipients were humanely killed at predetermined postoperative days 2–12 as well as 14 and 21. Histology was evaluated using hematoxylin-eosin (H&E) staining. We studied the expression of specific markers, including E-cadherin, an epithelial marker; α-smooth muscle actin (SMA), and S100A4, mesenchymal markers, and zinc finger E-box-binding homeobox 1 (ZEB1), an EMT-related transcription factor. Results: Histologic assessment of serial H&E stains of allogeneic grafts showed remarkable pseudostratified respiratory epithelium with subepithelial inflammatory cell infiltration, as well as denuded and flattened epithelium and subepithelial fibrosis. The dynamic epithelial changes occurred earlier than the subepithelial fibrosis. Immunohistochemical evaluation indicated the emergence of α-SMA– positive epithelial cells that were most prominent on day 7. The expression of E-cadherin was attenuated in α-SMA–positive epithelial cells. S100A4 was also expressed in epithelial cells. A few days before the intraepithelial expression of α-SMA, ZEB1 emerged in the nuclei of epithelial cells. Conclusions: We observed expression of an EMT-related transcription factor and mesenchymal markers along with the attenuation of epithelial marker expression in epithelial cells, several days before prominent subepithelial fibrosis formation, results that suggest epithelial cells to play an important fibrosis role in airway remodeling during epithelial to mesenchymal transition. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
8. TGF-β-induced apoptosis of B-cell lymphoma Ramos cells through reduction of MS4A1/CD20.
- Author
-
Kawabata, K C, Ehata, S, Komuro, A, Takeuchi, K, and Miyazono, K
- Subjects
- *
TRANSFORMING growth factors-beta , *APOPTOSIS , *B cell lymphoma , *LYMPHOMAS , *CANCER cells , *EPSTEIN-Barr virus , *OLIGONUCLEOTIDE arrays - Abstract
Transforming growth factor-β (TGF-β) exhibits growth inhibitory effects on various types of tumor cells, including B-cell lymphoma cells. In the present study, the role of TGF-β in the survival of Epstein-Barr virus-negative B-cell lymphoma Ramos cells was investigated. As TGF-β-induced apoptosis of Ramos cells in vitro and in vivo, we attempted to identify novel target gene(s) responsible for their survival. Oligonucleotide microarray analysis and chromatin immunoprecipitation revealed that Smad proteins directly regulated the transcription of membrane-spanning 4-domains, subfamily A, member 1 (MS4A1), also known as CD20, in Ramos cells upon TGF-β stimulation. In addition, immunohistochemical analysis using clinical samples from B-cell lymphoma patients showed an inverse correlation between the expression of MS4A1/CD20 and phosphorylation of Smad3. Although knockdown of MS4A1/CD20 in Ramos cells resulted in an increase of apoptotic cells, Ramos cells stably expressing MS4A1/CD20 were resistant to TGF-β-induced apoptosis. This suggests that MS4A1/CD20 is responsible for TGF-β-induced apoptosis of B-cell lymphoma cells. Moreover, downregulation of MS4A1/CD20 by TGF-β attenuated the effects of the monoclonal anti-MS4A1/CD20 antibody, rituximab, on Ramos cells. Our findings suggest that the sensitivity of B-cell lymphoma cells to rituximab may be affected by TGF-β signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
9. TGF-β drives epithelial-mesenchymal transition through δEF1-mediated downregulation of ESRP.
- Author
-
Horiguchi, K, Sakamoto, K, Koinuma, D, Semba, K, Inoue, A, Inoue, S, Fujii, H, Yamaguchi, A, Miyazawa, K, Miyazono, K, and Saitoh, M
- Subjects
- *
TRANSFORMING growth factors-beta , *EPITHELIUM , *MESENCHYMAL stem cells , *ELONGATION factors (Biochemistry) , *CANCER invasiveness , *CELL lines , *BREAST cancer , *FIBROBLAST growth factors - Abstract
Epithelial-mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair and cancer progression in adult tissues. We have recently shown that transforming growth factor (TGF)-β-induced EMT involves isoform switching of fibroblast growth factor receptors by alternative splicing. We performed a microarray-based analysis at single exon level to elucidate changes in splicing variants generated during TGF-β-induced EMT, and found that TGF-β induces broad alteration of splicing patterns by downregulating epithelial splicing regulatory proteins (ESRPs). This was achieved by TGF-β-mediated upregulation of δEF1 family proteins, δEF1 and SIP1. δEF1 and SIP1 each remarkably repressed ESRP2 transcription through binding to the ESRP2 promoter in NMuMG cells. Silencing of both δEF1 and SIP1, but not either alone, abolished the TGF-β-induced ESRP repression. The expression profiles of ESRPs were inversely related to those of δEF1 and SIP in human breast cancer cell lines and primary tumor specimens. Further, overexpression of ESRPs in TGF-β-treated cells resulted in restoration of the epithelial splicing profiles as well as attenuation of certain phenotypes of EMT. Therefore, δEF1 family proteins repress the expression of ESRPs to regulate alternative splicing during TGF-β-induced EMT and the progression of breast cancers. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
10. Polymeric micelles incorporating (1,2-diaminocyclohexane)platinum (II) suppress the growth of orthotopic scirrhous gastric tumors and their lymph node metastasis
- Author
-
Rafi, Md., Cabral, H., Kano, M.R., Mi, P., Iwata, C., Yashiro, M., Hirakawa, K., Miyazono, K., Nishiyama, N., and Kataoka, K.
- Subjects
- *
MICELLES , *PLATINUM compounds , *STOMACH cancer , *METASTASIS , *LYMPH node cancer , *DRUG carriers , *FIBROSIS - Abstract
Abstract: Nano-scaled drug carriers have great potential for the treatment of solid tumors. Nevertheless, hypovascularity and fibrosis in some types of solid tumors have been demonstrated to reduce the penetration and accumulation of nano-scaled drug carriers. Diffuse-type scirrhous gastric cancers present such characteristics as well as frequent metastasis to the lymph nodes; therefore, it remains a great challenge to eradicate scirrhous gastric cancers based on the drug targeting using nanocarriers. Herein, we demonstrated that polymeric micelles with 30-nm diameter incorporating (1,2-diaminocyclohexane)platinum(II) (DACHPt), the parent complex of the anticancer drug oxaliplatin, efficiently penetrated and accumulated in an orthotopic scirrhous gastric cancer model, leading to the inhibition of the tumor growth. Moreover, the elevated localization of systemically injected DACHPt-loaded micelles in metastastic lymph nodes reduced the metastatic tumor growth. These results suggest DACHPt-loaded micelles as a promising nanocarrier for the treatment of scirrhous gastric cancers and their lymphatic metastases. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
11. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size.
- Author
-
Cabral, H., Matsumoto, Y., Mizuno, K., Chen, Q., Murakami, M., Kimura, M., Terada, Y., Kano, M. R., Miyazono, K., Uesaka, M., Nishiyama, N., and Kataoka, K.
- Subjects
- *
MICELLES , *CANCER research , *DRUG delivery systems , *ANTINEOPLASTIC agents , *GROWTH factors - Abstract
A major goal in cancer research is to develop carriers that can deliver drugs effectively and without side effects. Liposomal and particulate carriers with diameters of ?100 nm have been widely used to improve the distribution and tumour accumulation of cancer drugs, but so far they have only been effective for treating highly permeable tumours. Here, we compare the accumulation and effectiveness of different sizes of long-circulating, drug-loaded polymeric micelles (with diameters of 30, 50, 70 and 100 nm) in both highly and poorly permeable tumours. All the polymer micelles penetrated highly permeable tumours in mice, but only the 30 nm micelles could penetrate poorly permeable pancreatic tumours to achieve an antitumour effect. We also showed that the penetration and efficacy of the larger micelles could be enhanced by using a transforming growth factor-? inhibitor to increase the permeability of the tumours. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
12. Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells.
- Author
-
Ehata, S, Johansson, E, Katayama, R, Koike, S, Watanabe, A, Hoshino, Y, Katsuno, Y, Komuro, A, Koinuma, D, Kano, M R, Yashiro, M, Hirakawa, K, Aburatani, H, Fujita, N, and Miyazono, K
- Subjects
- *
TRANSFORMING growth factors , *CELL populations , *STOMACH cancer , *CANCER cells , *STEM cells , *TISSUE analysis , *GENETIC regulation - Abstract
Stem cells in normal tissues and cancer-initiating cells (CICs) are known to be enriched in side population (SP) cells. However, the factors responsible for the regulation of expression of ABCG2, involved in efflux of dyes, in SP cells have not been fully investigated. Here, we characterized the SP cells within diffuse-type gastric carcinoma, and examined the effects of transforming growth factor-β (TGF-β) on SP cells. Diffuse-type gastric carcinoma cells established from four independent patients universally contained SP cells between 1 and 4% of total cells, which displayed greater tumorigenicity than non-SP cells did. TGF-β repressed the transcription of ABCG2 through direct binding of Smad2/3 to its promoter/enhancer, and the number of SP cells and the tumor-forming ability of cancer cells were decreased by TGF-β, although ABCG2 is not directly involved in the tumor-forming ability of SP cells. Cancer cells from metastatic site expressed much higher levels of ABCG2 and included a greater percentage of SP cells than parental cancer cells did. SP cells are thus responsible for the progression of diffuse-type gastric carcinoma, and TGF-β negatively contributes to maintain the CICs within the cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
13. Diffuse-type gastric carcinoma: progression, angiogenesis, and transforming growth factor beta signaling.
- Author
-
Komuro A, Yashiro M, Iwata C, Morishita Y, Johansson E, Matsumoto Y, Watanabe A, Aburatani H, Miyoshi H, Kiyono K, Shirai YT, Suzuki HI, Hirakawa K, Kano MR, Miyazono K, Komuro, Akiyoshi, Yashiro, Masakazu, Iwata, Caname, Morishita, Yasuyuki, and Johansson, Erik
- Abstract
Background: Diffuse-type gastric carcinoma is a cancer with poor prognosis that has high levels of transforming growth factor beta (TGF-beta) expression and thick stromal fibrosis. However, the association of TGF-beta signaling with diffuse-type gastric carcinoma has not been investigated in detail.Methods: We used a lentiviral infection system to express a dominant-negative TGF-beta type II receptor (dnTbetaRII) or green fluorescent protein (GFP) as a control in the diffuse-type gastric carcinoma cell lines, OCUM-2MLN and OCUM-12. These infected cells and the corresponding parental control cells were subcutaneously or orthotopically injected into nude mice. Angiogenesis was inhibited by infecting cells with a lentivirus carrying the gene for angiogenic inhibitor thrombospondin-1 or by injecting mice intraperitoneally with the small-molecule angiogenic inhibitor sorafenib or with anti-vascular endothelial growth factor (VEGF) neutralizing antibody (six or eight mice per group). Expression of phospho-Smad2 and thrombospondin-1 was investigated immunologically in human gastric carcinoma tissues from 102 patients. All statistical tests were two-sided.Results: Expression of dnTbetaRII into OCUM-2MLN cells did not affect their proliferation in vitro, but it accelerated the growth of subcutaneously or orthotopically transplanted tumors in vivo (eg, for mean volume of subcutaneous tumors on day 10 relative to that on day 0: dnTbetaRII tumors = 3.49 and GFP tumors = 2.46, difference = 1.02, 95% confidence interval [CI] = 0.21 to 1.84; P = .003). The tumors expressing dnTbetaRII had higher levels of angiogenesis than those expressing GFP because of decreased thrombospondin-1 production. Similar results were obtained with OCUM-12 cells. Expression of thrombospondin-1 in the dnTbetaRII tumor or treatment with sorafenib or anti-VEGF antibody reduced tumor growth, whereas knockdown of thrombospondin-1 expression resulted in more accelerated growth of OCUM-2MLN tumors than of GFP tumors (eg, mean tumor volumes on day 14 relative to those on day 0: thrombospondin-1-knockdown tumors = 4.91 and GFP tumors = 3.79, difference = 1.12, 95% CI = 0.80 to 1.44; P < .001). Positive association between phosphorylated Smad2 and thrombospondin-1 immunostaining was observed in human gastric carcinoma tissues.Conclusions: Disruption of TGF-beta signaling in diffuse-type gastric carcinoma models appeared to accelerate tumor growth, apparently through increased tumor angiogenesis that was induced by decreased expression of thrombospondin-1. [ABSTRACT FROM AUTHOR]- Published
- 2009
- Full Text
- View/download PDF
14. Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway.
- Author
-
Katsuno, Y, Hanyu, A, Kanda, H, Ishikawa, Y, Akiyama, F, Iwase, T, Ogata, E, Ehata, S, Miyazono, K, and Imamura, T
- Subjects
- *
METASTASIS , *CANCER invasiveness , *CANCER , *BONE metastasis , *TUMORS - Abstract
Transforming growth factor (TGF)-β is known to promote tumor invasion and metastasis. Although bone morphogenetic proteins (BMPs), members of the TGF-β family, are expressed in a variety of human carcinoma cell lines, their roles in tumor progression have not been fully clarified. In this study, we sought to determine the roles of BMPs in the progression of breast cancer bone metastasis using human breast cancer samples and a mouse xenograft model. Immunohistochemical analysis of samples from breast cancer patients as well as a mouse xenograft model of MDA-231-D, highly metastatic human breast cancer cells, revealed phospho-Smad2 and phospho-Smad1/5/8 staining in the nuclei of cancer cells in primary tumor and/or bone metastasis. Using a functional in vivo bioluminescence imaging system, we showed that TGF-β- and BMP-induced transcriptional pathways are active in bone metastatic lesions in vivo. In addition, both TGF-β3 and BMP-2 promoted the motility and invasiveness of the MDA-231-D cells in vitro. Moreover, expression of dominant-negative receptors for TGF-β and/or BMPs in the MDA-231-D cells inhibited invasiveness in vitro and bone metastasis in the xenograft model. These results suggest that BMPs as well as TGF-β promote invasion and bone metastasis of breast cancer.Oncogene (2008) 27, 6322–6333; doi:10.1038/onc.2008.232; published online 28 July 2008 [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
15. Modulation of the functional binding sites for TGF-β on the type II receptor leads to suppression of TGF-β signaling.
- Author
-
Shimanuki, T., Hara, T., Furuya, T., Imamura, T., and Miyazono, K.
- Subjects
- *
CELL transformation , *TRANSFORMING growth factors-beta , *SERINE proteinases , *CELL receptors , *PHOSPHORYLATION , *AMINO acid sequence - Abstract
Transforming growth factor-β (TGF-β) binds to two different types of serine/threonine kinase receptors termed type II (TβR-II) and type I (TβR-I). TGF-β is unable to bind to TβR-I in the absence of TβR-II, and initiates receptor assembly by binding with high affinity to TβR-II. Previous structural analysis of the TGF-β3–TβR-II complex has suggested that two charged amino acid residues, D55 and E142 of TβR-II, are binding sites of TGF-β. In the present study, we have shown that mutations of the amino-acid residues, D55 and E142 of TβR-II, resulted in loss of TGF-β binding and downstream signaling activity. Moreover, we found that 3,5,7,2′,4′-pentahydroxyflavone (Morin) inhibits TGF-β binding to TβR-II, and suppresses phosphorylation of Smad2 and expression of a TGF-β target gene Smad7 induced by TGF-β. Our findings may thus provide useful information for designing therapeutic agents for various diseases induced by TGF-β, including advanced cancers.Oncogene (2007) 26, 3311–3320. doi:10.1038/sj.onc.1210123; published online 4 December 2006 [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
16. Execution of BMP-4-induced apoptosis by p53-dependent ER dysfunction in myeloma and B-cell hybridoma cells.
- Author
-
Fukuda, N., Saitoh, M., Kobayashi, N., and Miyazono, K.
- Subjects
- *
APOPTOSIS , *GENES , *MULTIPLE myeloma , *ENDOPLASMIC reticulum , *ORGANELLES , *HYBRIDOMAS - Abstract
Bone morphogenic protein (BMP)-4 inhibits proliferation and induces the apoptosis of myeloma cells. However, little is known about the molecular mechanisms of how BMP-4 executes this apoptosis. In this report, we investigated the roles of p53 and the endoplasmic reticulum (ER) in BMP-4-induced apoptosis of mouse hybridoma HS-72 cells. We found that 3 ng/ml of BMP-4 is sufficient to induce the expression of proapoptotic proteins, puma and bax, in a p53-dependent mechanism, and facilitate Ca2+ release from the ER to the cytosol, resulting in the activation of caspase-12 and ER dysfunction. Similarly to HS-72 cells, multiple myeloma cells with wild-type p53 genes show much higher sensitivity to BMP-4-induced apoptosis than cells without wild-type p53 genes, suggesting that wild-type p53 status is required for dysfunction of the ER during BMP-4-induced apoptosis in ER-enriched cells, such as hybridoma and myeloma cells. These findings demonstrate that the presence of wild-type p53 genes and enrichment of the ER determines the sensitivity to effective apoptosis by BMP-4, and suggest that ER stress-inducing agents would be valuable in the treatment of multiple myeloma.Oncogene (2006) 25, 3509–3517. doi:10.1038/sj.onc.1209393; published online 30 January 2006 [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
17. A role for Id in the regulation of TGF-ß-induced epithelial-mesenchymal transdifferentiation.
- Author
-
Kondo, M., Cubillo, E., Tobiume, K., Shirakihara, T., Fukuda, N., Suzuki, H., Shimizu, K., Takehara, K., Cano, A., Saitoh, M., and Miyazono, K.
- Subjects
- *
TRANSFORMING growth factors , *PROTEINS , *EMBRYOLOGY , *EPITHELIAL cells , *CYTOLOGY , *TUMORS - Abstract
Epithelial-mesenchymal transdifferentiation (EMT) is a critical morphogenic event that occurs during embryonic development and during the progression of various epithelial tumors. EMT can be induced by transforming growth factor (TGF)-ßin mouse NMuMG mammary epithelial cells. Here, we demonstrate a central role of helix-loop-helix factors, E2A and inhibitor of differentiation (Id) proteins, in TGF-ß-induced EMT. Epithelial cells ectopically expressing E2A adopt a fibroblastic phenotype and acquire migratory/invasive properties, concomitant with the suppression of E-cadherin expression. Id proteins interacted with E2A proteins and antagonized E2A-dependent suppression of the E-cadherin promoter. Levels of Id proteins were dramatically decreased by TGF-ß. Moreover, NMuMG cells overexpressed Id2 showed partial resistance to TGF-ß-induced EMT. Id proteins thus inhibit the action of E2A proteins on the expression of E-cadherin, but after TGF-ßstimulation, E2A proteins are present in molar excess of the Id proteins, thus over-riding their inhibitory function and leading to EMT.Cell Death and Differentiation (2004) 11, 1092-1101. doi:10.1038/sj.cdd.4401467 Published online 4 June 2004 [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.