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Okio Hino - One of the best experts on this subject based on the ideXlab platform.

  • models for genitourinary cancer hereditary Renal Carcinogenesis
    The Cancer Handbook, 2007
    Co-Authors: Okio Hino
    Abstract:

    The Eker (Tsc2 gene mutant) rat model of hereditary Renal carcinoma (RC) is an example of Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. Recently, we discovered a new hereditary RC in the Japanese rat, which was named the “Nihon” rat. The predisposing (Bhd) gene could be a novel Renal tumour-suppressor gene. We present these unique models for the study of problems in Renal Carcinogenesis. Keywords: hereditary Renal cancer; Knudson's two-hit; Tsc2 gene (Eker) mutant; Bhd gene (Nihon) mutant; Tsc1 gene; Niban gene; Erc gene

  • The Cancer Handbook - Models for Genitourinary Cancer – Hereditary Renal Carcinogenesis
    The Cancer Handbook, 2007
    Co-Authors: Okio Hino
    Abstract:

    The Eker (Tsc2 gene mutant) rat model of hereditary Renal carcinoma (RC) is an example of Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. Recently, we discovered a new hereditary RC in the Japanese rat, which was named the “Nihon” rat. The predisposing (Bhd) gene could be a novel Renal tumour-suppressor gene. We present these unique models for the study of problems in Renal Carcinogenesis. Keywords: hereditary Renal cancer; Knudson's two-hit; Tsc2 gene (Eker) mutant; Bhd gene (Nihon) mutant; Tsc1 gene; Niban gene; Erc gene

  • N-terminal hamartin-binding and C-terminal GAP domain of tuberin can separate in vivo.
    Biochemical and biophysical research communications, 2007
    Co-Authors: Shuji Momose, Toshiyuki Kobayashi, Norihiro Tada, Shinji Itoyama, Okio Hino
    Abstract:

    Abstract The Eker rat is an animal model of Renal Carcinogenesis and carries a transposon insertion in the Tsc2 (tuberous sclerosis-2) gene. We previously generated transgenic Eker rats and identified coding sequences in the Tsc2 gene that are responsible for suppression of Renal Carcinogenesis in Eker rats. Tsc2-RGH, a transgene that expresses the carboxy terminal region (amino acids 1425–1755) of the Tsc2 product (tuberin), partially suppressed Renal Carcinogenesis. However, Tsc2-DRG, which expresses a mutant tuberin lacking the carboxy-terminal region (Δaa 1425–1755), did not suppress Renal Carcinogenesis. Here, we found that introduction of both Tsc2-RGH and Tsc2-DRG in Eker rats completely suppressed Renal Carcinogenesis and rescued homozygous (Tsc2Ek/Ek) mutants from embryonic lethality in a complementary manner. Co-introduction of Tsc2-RGH and Tsc2-DRG, but not introduction of either alone, efficiently suppressed phosphorylation of p70 S6K. Thus, the functional domains of N-terminal hamartin binding and C-terminal tumor suppression in tuberin can separate in vivo.

  • A novel tumor marker, Niban, is expressed in subsets of thyroid tumors and Hashimoto's thyroiditis.
    Human pathology, 2006
    Co-Authors: Fumihiko Matsumoto, Toshiyuki Kobayashi, Kazunori Kajino, Masaaki Abe, Hiroaki Fujii, Toshiharu Matsumoto, Katsuhisa Ikeda, Okio Hino
    Abstract:

    Niban is a recently identified molecular marker of Renal Carcinogenesis in the Tsc2 gene-mutant Eker rat. Niban expression is most dramatically increased in the early stage of Renal Carcinogenesis and might decline during malignant progression. Niban is also expressed in various histologic types of human Renal cell carcinoma. Therefore, Niban might be a good marker for Renal Carcinogenesis in both animal models and humans. In the present study, we examined Niban expression in various thyroid lesions by immunohistochemical staining using polyclonal rabbit antihuman Niban antibody. Normal thyroid tissue never stained for Niban. Niban was most frequently expressed in tumors with oxyphilic cytoplasm, including oxyphilic variants of papillary carcinoma (4/4 = 100%), oxyphilic variants of follicular adenoma (7/7 = 100%), and oxyphilic variants of follicular carcinoma (5/5 = 100%). Eighty-one percent (44/54) of papillary carcinoma cases, including microcarcinomas, and follicular variants were also positively stained for Niban at variable intensities. Follicular carcinomas were less frequently and less intensely stained. In nonneoplastic lesions, cells were rarely positively stained. In Hashimoto's thyroiditis, scattered cells with oxyphilic cell metaplasia were weakly Niban-positive. Reverse transcriptase-polymerase chain reaction and Western blot analysis of frozen tissue confirmed Niban expression at the molecular level in 4 cases of papillary carcinoma. Taken together, Niban expression is up-regulated in various types of thyroid tumors. We postulate that Niban expression may play an important role in the tumorigenic process of the thyroid in several scenarios. (1) Niban expression may be closely related to the carcinogenic process, especially from the early stage of papillary thyroid carcinoma. (2) Niban may be closely associated with altered mitochondrial functions in preneoplastic and neoplastic processes of the thyroid. (3) Niban may be a molecular marker of the oxyphilic phenotype under various conditions. Further functional studies of Niban will clarify the role of Niban in various thyroid lesions.

  • Transgenic rescue from embryonic lethality and Renal Carcinogenesis in the Nihon rat model by introduction of a wild-type Bhd gene
    Oncogene, 2005
    Co-Authors: Yuki Togashi, Toshiyuki Kobayashi, Shuji Momose, Kazuo Okimoto, M Ueda, Okio Hino
    Abstract:

    We recently reported that a germline insertion of a single nucleotide in the rat homologue of the human Birt-Hogg-Dube gene (BHD) gives rise to dominantly inherited cancer in the Nihon rat model. In this study, we constructed transgenic Nihon rats with introduction of a wild-type Bhd gene to ascertain whether suppression of the Nihon phenotype is possible. Rescue from embryonic lethality of mutant homozygotes (Nihon/Nihon) and suppression of Renal Carcinogenesis in heterozygotes (Nihon/+) were both observed, defining the germline Bhd mutation in the Nihon rat as an embryonal lethal and tumor predisposing mutation. This transgenic rescue system will be useful to analyse Bhd gene function, its relation to tumorigenesis in vivo, and genetic-environmental interactions in Carcinogenesis.

Toshiyuki Kobayashi - One of the best experts on this subject based on the ideXlab platform.

  • deficiency of the erc mesothelin gene ameliorates Renal Carcinogenesis in tsc2 knockout mice
    Cancer Science, 2011
    Co-Authors: Danqing Zhang, Toshiyuki Kobayashi, Tetsuo Kojima, Kenji Kanenishi, Yoshiaki Hagiwara, Masaaki Abe, Hidehiro Okura, Yoshitomo Hamano, Guodong Sun, Masahiro Maeda
    Abstract:

    Genetic crossing experiments were performed between tuberous sclerosis-2 (Tsc2) KO and expressed in Renal carcinoma (Erc) KO mice to analyze the function of the Erc/mesothelin gene in Renal Carcinogenesis. We found the number and size of Renal tumors were significantly less in Tsc2+/-;Erc-/- mice than in Tsc2+/-;Erc+/+ and Tsc2+/-;Erc+/- mice. Tumors from Tsc2+/-;Erc-/- mice exhibited reduced cell proliferation and increased apoptosis, as determined by proliferating cell nuclear antigen (Ki67) and TUNEL analysis, respectively. Adhesion to collagen-coated plates in vitro was enhanced in Erc-restored cells and decreased in Erc-suppressed cells with siRNA. Tumor formation by Tsc2-deficient cells in nude mice was remarkably suppressed by stable knockdown of Erc with shRNA. Western blot analysis showed that the phosphorylation of focal adhesion kinase, Akt and signal transducer and activator of transcription protein 3 were weaker in Erc-deficient/suppressed cells compared with Erc-expressed cells. These results indicate that deficiency of the Erc/mesothelin gene ameliorates Renal Carcinogenesis in Tsc2 KO mice and inhibits the phosphorylation of several kinases of cell adhesion mechanism. This suggests that Erc/mesothelin may have an important role in the promotion and/or maintenance of Carcinogenesis by influencing cell-substrate adhesion via the integrin-related signal pathway.

  • Deficiency of the Erc/mesothelin gene ameliorates Renal Carcinogenesis in Tsc2 knockout mice
    Cancer science, 2011
    Co-Authors: Danqing Zhang, Toshiyuki Kobayashi, Tetsuo Kojima, Kenji Kanenishi, Yoshiaki Hagiwara, Masaaki Abe, Hidehiro Okura, Yoshitomo Hamano, Guodong Sun, Masahiro Maeda
    Abstract:

    Genetic crossing experiments were performed between tuberous sclerosis-2 (Tsc2) KO and expressed in Renal carcinoma (Erc) KO mice to analyze the function of the Erc/mesothelin gene in Renal Carcinogenesis. We found the number and size of Renal tumors were significantly less in Tsc2+/-;Erc-/- mice than in Tsc2+/-;Erc+/+ and Tsc2+/-;Erc+/- mice. Tumors from Tsc2+/-;Erc-/- mice exhibited reduced cell proliferation and increased apoptosis, as determined by proliferating cell nuclear antigen (Ki67) and TUNEL analysis, respectively. Adhesion to collagen-coated plates in vitro was enhanced in Erc-restored cells and decreased in Erc-suppressed cells with siRNA. Tumor formation by Tsc2-deficient cells in nude mice was remarkably suppressed by stable knockdown of Erc with shRNA. Western blot analysis showed that the phosphorylation of focal adhesion kinase, Akt and signal transducer and activator of transcription protein 3 were weaker in Erc-deficient/suppressed cells compared with Erc-expressed cells. These results indicate that deficiency of the Erc/mesothelin gene ameliorates Renal Carcinogenesis in Tsc2 KO mice and inhibits the phosphorylation of several kinases of cell adhesion mechanism. This suggests that Erc/mesothelin may have an important role in the promotion and/or maintenance of Carcinogenesis by influencing cell-substrate adhesion via the integrin-related signal pathway.

  • N-terminal hamartin-binding and C-terminal GAP domain of tuberin can separate in vivo.
    Biochemical and biophysical research communications, 2007
    Co-Authors: Shuji Momose, Toshiyuki Kobayashi, Norihiro Tada, Shinji Itoyama, Okio Hino
    Abstract:

    Abstract The Eker rat is an animal model of Renal Carcinogenesis and carries a transposon insertion in the Tsc2 (tuberous sclerosis-2) gene. We previously generated transgenic Eker rats and identified coding sequences in the Tsc2 gene that are responsible for suppression of Renal Carcinogenesis in Eker rats. Tsc2-RGH, a transgene that expresses the carboxy terminal region (amino acids 1425–1755) of the Tsc2 product (tuberin), partially suppressed Renal Carcinogenesis. However, Tsc2-DRG, which expresses a mutant tuberin lacking the carboxy-terminal region (Δaa 1425–1755), did not suppress Renal Carcinogenesis. Here, we found that introduction of both Tsc2-RGH and Tsc2-DRG in Eker rats completely suppressed Renal Carcinogenesis and rescued homozygous (Tsc2Ek/Ek) mutants from embryonic lethality in a complementary manner. Co-introduction of Tsc2-RGH and Tsc2-DRG, but not introduction of either alone, efficiently suppressed phosphorylation of p70 S6K. Thus, the functional domains of N-terminal hamartin binding and C-terminal tumor suppression in tuberin can separate in vivo.

  • A novel tumor marker, Niban, is expressed in subsets of thyroid tumors and Hashimoto's thyroiditis.
    Human pathology, 2006
    Co-Authors: Fumihiko Matsumoto, Toshiyuki Kobayashi, Kazunori Kajino, Masaaki Abe, Hiroaki Fujii, Toshiharu Matsumoto, Katsuhisa Ikeda, Okio Hino
    Abstract:

    Niban is a recently identified molecular marker of Renal Carcinogenesis in the Tsc2 gene-mutant Eker rat. Niban expression is most dramatically increased in the early stage of Renal Carcinogenesis and might decline during malignant progression. Niban is also expressed in various histologic types of human Renal cell carcinoma. Therefore, Niban might be a good marker for Renal Carcinogenesis in both animal models and humans. In the present study, we examined Niban expression in various thyroid lesions by immunohistochemical staining using polyclonal rabbit antihuman Niban antibody. Normal thyroid tissue never stained for Niban. Niban was most frequently expressed in tumors with oxyphilic cytoplasm, including oxyphilic variants of papillary carcinoma (4/4 = 100%), oxyphilic variants of follicular adenoma (7/7 = 100%), and oxyphilic variants of follicular carcinoma (5/5 = 100%). Eighty-one percent (44/54) of papillary carcinoma cases, including microcarcinomas, and follicular variants were also positively stained for Niban at variable intensities. Follicular carcinomas were less frequently and less intensely stained. In nonneoplastic lesions, cells were rarely positively stained. In Hashimoto's thyroiditis, scattered cells with oxyphilic cell metaplasia were weakly Niban-positive. Reverse transcriptase-polymerase chain reaction and Western blot analysis of frozen tissue confirmed Niban expression at the molecular level in 4 cases of papillary carcinoma. Taken together, Niban expression is up-regulated in various types of thyroid tumors. We postulate that Niban expression may play an important role in the tumorigenic process of the thyroid in several scenarios. (1) Niban expression may be closely related to the carcinogenic process, especially from the early stage of papillary thyroid carcinoma. (2) Niban may be closely associated with altered mitochondrial functions in preneoplastic and neoplastic processes of the thyroid. (3) Niban may be a molecular marker of the oxyphilic phenotype under various conditions. Further functional studies of Niban will clarify the role of Niban in various thyroid lesions.

  • Transgenic rescue from embryonic lethality and Renal Carcinogenesis in the Nihon rat model by introduction of a wild-type Bhd gene
    Oncogene, 2005
    Co-Authors: Yuki Togashi, Toshiyuki Kobayashi, Shuji Momose, Kazuo Okimoto, M Ueda, Okio Hino
    Abstract:

    We recently reported that a germline insertion of a single nucleotide in the rat homologue of the human Birt-Hogg-Dube gene (BHD) gives rise to dominantly inherited cancer in the Nihon rat model. In this study, we constructed transgenic Nihon rats with introduction of a wild-type Bhd gene to ascertain whether suppression of the Nihon phenotype is possible. Rescue from embryonic lethality of mutant homozygotes (Nihon/Nihon) and suppression of Renal Carcinogenesis in heterozygotes (Nihon/+) were both observed, defining the germline Bhd mutation in the Nihon rat as an embryonal lethal and tumor predisposing mutation. This transgenic rescue system will be useful to analyse Bhd gene function, its relation to tumorigenesis in vivo, and genetic-environmental interactions in Carcinogenesis.

Sarwat Sultana - One of the best experts on this subject based on the ideXlab platform.

  • Chrysin Suppresses Development of Precancerous Lesions in Kidneys by Regulation of Oxidative Stress, Inflammation, Hyperproliferation and Apoptosis in Murine Model
    Free Radical Biology and Medicine, 2016
    Co-Authors: Sarwat Sultana, Summya Rashid
    Abstract:

    Chrysin (CH) is a natural compound which belongs to flavonoid family and possesses diverse pharmacological activities like anti-inflammatory, anti-oxidant and anti-cancer. It is found in many plants, honey and propolis. In the present study, we investigated the chemopreventive efficacy of CH against N-nitrosodiethylamine (DEN) initiated and Fe-NTA induced Renal Carcinogenesis and its role in regulating oxidative injury, histopathological alterations, ultra structural changes, inflammation, hyper proliferation, tumor incidences and apoptosis in the kidneys of Wistar rats. Renal cancer was initiated by single intraperitoneal (i.p.) injection of DEN (200mg/kg b.w) and promoted by twice weekly injection of ferric nitrilotriacetate (Fe-NTA) 9 mg Fe/kg bw for 16 weeks. CH attenuated oxidative injury induced by DEN and Fe-NTA administration. CH supplementation suppressed the development of Renal Carcinogenesis induced by DEN initiation and Fe-NTA promotion via down regulation of cell proliferation marker like PCNA; tumor incidences and inflammatory mediators like TNF-α, IL-6, NFkB, Cox-2, iNOS. CH up regulated intrinsic apoptotic pathway proteins like bax, bcl-2, caspase-9 and caspase-3 triggering apoptosis. Histopathological and ultra structural alterations further supported our previous findings. Henceforth our results provide a powerful evidence for the chemopreventive efficacy of CH against chemically induced Renal Carcinogenesis possibly by modulation of multiple molecular pathways.

  • Chemopreventive efficacy of hesperidin against chemically induced nephrotoxicity and Renal Carcinogenesis via amelioration of oxidative stress and modulation of multiple molecular pathways.
    Experimental and molecular pathology, 2015
    Co-Authors: Aisha Siddiqi, Summya Rashid, Sana Nafees, Syed Kazim Hasan, Bano Saidullah, Sarwat Sultana
    Abstract:

    In the present study, chemopreventive efficacy of hesperidin was evaluated against ferric nitrilotriacetate (Fe-NTA) induced Renal oxidative stress and Carcinogenesis in wistar rats. Nephrotoxicity was induced by single intraperitoneal injection of Fe-NTA (9 mg Fe/kg b.wt). Renal cancer was initiated by the administration of N-nitrosodiethylamine (DEN 200mg/kg b.wt ip) and promoted by Fe-NTA (9 mg Fe/kg b.wt ip) twice weekly for 16 weeks. Efficacy of hesperidin against Fe-NTA-induced nephrotoxicity was assessed in terms of biochemical estimation of antioxidant enzyme activities viz. reduced Renal GSH, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, catalase, superoxide dismutase and Renal toxicity markers (BUN, Creatinine, KIM-1). Administration of Fe-NTA significantly depleted antioxidant Renal armory, enhanced Renal lipid peroxidation as well as the levels of BUN, creatinine and KIM-1. However, simultaneous pretreatment of hesperidin restored their levels in a dose dependent manner. Expression of apoptotic markers caspase-3, caspase-9, bax, bcl-2 and proliferative marker PCNA along with inflammatory markers (NFκB, iNOS, TNF-α) were also analysed to assess the chemopreventive potential of hesperidin in two-stage Renal Carcinogenesis model. Hesperidin was found to induce caspase-3, caspase-9, bax expression and downregulate bcl-2, NFκB, iNOS, TNF-α, PCNA expression. Histopathological findings further revealed hesperidin's chemopreventive efficacy by restoring the Renal morphology. Our results provide a powerful evidence suggesting hesperidin to be a potent chemopreventive agent against Renal Carcinogenesis possibly by virtue of its antioxidant properties and by modulation of multiple molecular pathways.

  • modulation of chemically induced Renal Carcinogenesis by chrysin via inhibition of oxidative stress hyper proliferation and inflammation at preclinical stage
    Journal for ImmunoTherapy of Cancer, 2015
    Co-Authors: Summya Rashid, Sarwat Sultana
    Abstract:

    Meeting abstracts The present study was planned to investigate the chemopreventive efficacy of Chrysin (CH) against Renal Carcinogenesis in Wistar rats. Ferric nitrilotriacetate (Fe-NTA) is a potent nephrotoxicant and known Renal carcinogen. CH is a natural flavonoid found in honey, propolis, blue

  • Amelioration of Renal Carcinogenesis by bee propolis: a chemo preventive approach.
    Toxicology international, 2013
    Co-Authors: Summya Rashid, Nemat Ali, Sana Nafees, Syed Kazim Hasan, Sarwat Sultana
    Abstract:

    Objective: The present study was designed to investigate the chemo preventive efficacy of bee propolis (BP) against diethylnitrosamine (DEN) initiated and ferric nitrilotriacetate (Fe-NTA) promoted Renal Carcinogenesis in Wistar rats. Chronic treatment of Fe-NTA induced oxidative stress, inflammation and cellular proliferation in Wistar rats. BP is a resinous material collected by bees from various plants which has been used from centuries in folk medicine. Materials and Methods: Renal cancer was initiated by single intraperitoneal injection of N-nitrosodiethylamine (DEN 200 mg/kg body weight) and promoted by twice weekly administration of Fe-NTA 9 mg Fe/kg body weight for 16 weeks. The chemo preventive efficacy of BP was studied in terms of lipid peroxidation (LPO), Renal anti-oxidant armory such as catalase, superoxide dismustase, glutathione S-transferase, glutathione peroxidase, glutathione reductase and glutathione (GSH), serum toxicity markers, cell proliferation, tumor suppressor protein and inflammation markers. Results: Administration of Fe-NTA enhances Renal LPO, with concomitant reduction in reduced GSH content and antioxidant enzymes. It induces serum toxicity markers, viz., blood urea nitrogen, creatinine and lactate dehydrogenase. Chemo preventive effects of BP were associated with upregulation of antioxidant armory and down regulation of serum toxicity markers. BP was also able to down regulate expression of proliferative cell nuclear antigen, cyclooxygenase-2, tumor necrosis factor-alpha and upregulated p53 along with induction of apoptosis. Histopathological changes further confirmed the biochemical and immunohistochemical results. Conclusion: These results provide a powerful evidence for the chemo preventive efficacy of BP against Renal Carcinogenesis possibly by modulation of multiple molecular pathways.

  • Chrysin suppresses Renal Carcinogenesis via amelioration of hyperproliferation, oxidative stress and inflammation: plausible role of NF-κB.
    Toxicology letters, 2012
    Co-Authors: Muneeb U Rehman, Mir Tahir, Abdul Quaiyoom Khan, Rehan Khan, Abdul Lateef, Oday-o-hamiza, Wajhul Qamar, Farrah Ali, Sarwat Sultana
    Abstract:

    Flavonoid family is a rich source of polyphenolic compounds and hence possess strong antioxidant and anti inflammatory properties. The aim of this study was to determine the efficacy of chrysin; a bio-active flavonoid as an anticancer agent. Renal cancer was initiated by single intraperitoneal (i.p.) injection of N-nitrosodiethylamine (DEN 200 mg/kg BW body weight) and promoted by twice weekly administration of ferric nitrilotriacetate (Fe-NTA) 9 mg Fe/kg BW for 16 wk. In the present study, we report the chemopreventive effects of chrysin against (Fe-NTA) induced Renal oxidative stress, inflammation, hyperproliferative response, and two-stage Renal Carcinogenesis. To ascertain the molecular mechanism implicated in the antitumor promoting activity of chrysin, its effect was investigated on markers of tumor promotion and inflammation: ornithine decarboxylase (ODC) activity, proliferating cell nuclear antigen (PCNA), inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) expression, and on levels of proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and prostaglandin E(2) (PGE(2)). Pretreatment of animals with chrysin at both doses (20 and 40 mg/kg body weight) markedly inhibited all. Further, Fe-NTA enhances Renal lipid peroxidation, with concomitant reduction in reduced glutathione content (GSH), antioxidant enzymes, and phase II metabolizing enzymes. It induces serum toxicity markers, viz., blood urea nitrogen (BUN), creatinine and lactate dehydrogenase (LDH). Prophylactic treatment of animals with chrysin before the administration of Fe-NTA was effective in modulating oxidative and Renal injury markers and resulted in the diminution of Fe-NTA mediated injury. These results suggest chrysin as an effective chemopreventive agent having the capability to obstruct DEN initiated and Fe-NTA promoted Renal cancer in the rat model.

Shuji Momose - One of the best experts on this subject based on the ideXlab platform.

  • N-terminal hamartin-binding and C-terminal GAP domain of tuberin can separate in vivo.
    Biochemical and biophysical research communications, 2007
    Co-Authors: Shuji Momose, Toshiyuki Kobayashi, Norihiro Tada, Shinji Itoyama, Okio Hino
    Abstract:

    Abstract The Eker rat is an animal model of Renal Carcinogenesis and carries a transposon insertion in the Tsc2 (tuberous sclerosis-2) gene. We previously generated transgenic Eker rats and identified coding sequences in the Tsc2 gene that are responsible for suppression of Renal Carcinogenesis in Eker rats. Tsc2-RGH, a transgene that expresses the carboxy terminal region (amino acids 1425–1755) of the Tsc2 product (tuberin), partially suppressed Renal Carcinogenesis. However, Tsc2-DRG, which expresses a mutant tuberin lacking the carboxy-terminal region (Δaa 1425–1755), did not suppress Renal Carcinogenesis. Here, we found that introduction of both Tsc2-RGH and Tsc2-DRG in Eker rats completely suppressed Renal Carcinogenesis and rescued homozygous (Tsc2Ek/Ek) mutants from embryonic lethality in a complementary manner. Co-introduction of Tsc2-RGH and Tsc2-DRG, but not introduction of either alone, efficiently suppressed phosphorylation of p70 S6K. Thus, the functional domains of N-terminal hamartin binding and C-terminal tumor suppression in tuberin can separate in vivo.

  • Transgenic rescue from embryonic lethality and Renal Carcinogenesis in the Nihon rat model by introduction of a wild-type Bhd gene
    Oncogene, 2005
    Co-Authors: Yuki Togashi, Toshiyuki Kobayashi, Shuji Momose, Kazuo Okimoto, M Ueda, Okio Hino
    Abstract:

    We recently reported that a germline insertion of a single nucleotide in the rat homologue of the human Birt-Hogg-Dube gene (BHD) gives rise to dominantly inherited cancer in the Nihon rat model. In this study, we constructed transgenic Nihon rats with introduction of a wild-type Bhd gene to ascertain whether suppression of the Nihon phenotype is possible. Rescue from embryonic lethality of mutant homozygotes (Nihon/Nihon) and suppression of Renal Carcinogenesis in heterozygotes (Nihon/+) were both observed, defining the germline Bhd mutation in the Nihon rat as an embryonal lethal and tumor predisposing mutation. This transgenic rescue system will be useful to analyse Bhd gene function, its relation to tumorigenesis in vivo, and genetic-environmental interactions in Carcinogenesis.

  • Renal Carcinogenesis: genotype, phenotype and dramatype.
    Cancer science, 2003
    Co-Authors: Okio Hino, Hiroyuki Adachi, Toshiyuki Kobayashi, Y Kikuchi, Shuji Momose, Kazuo Okimoto
    Abstract:

    Cancer is a heritable disorder of somatic cells. Environment and heredity are both important in the carcinogenic process. The Eker rat model of hereditary Renal carcinoma (RC) is an example of a Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. Forty years after the discovery of the Eker rat in Oslo, we and Knudson's group independently identified a germline retrotransposon insertion in the rat homologue of the human tuberous sclerosis (TSC2) gene. To our knowledge, this was the first isolation of a Mendelian dominantly predisposing cancer gene in a naturally occurring animal model. Recently, we discovered a new hereditary Renal carcinoma in the rat. This rat was named the "Nihon" rat and its predisposing (Nihon) gene could be a novel Renal tumor suppressor gene. This article will review the utility of these unique models for the study of problems in Carcinogenesis; e.g., species-specific differences in tumorigenesis, cell stage and tissue/cell-type specific tumorigenesis, multistep Carcinogenesis, modifier gene(s) in Renal Carcinogenesis, cancer prevention and the development of therapeutic treatments which can be translated to human patients, as well as how environmental factors interact with cancer susceptibility gene(s).

  • Identification of the coding sequences responsible for Tsc2-mediated tumor suppression using a transgenic rat system
    Human molecular genetics, 2002
    Co-Authors: Shuji Momose, Toshiyuki Kobayashi, Hiroaki Mitani, M Ueda, Masumi Hirabayashi, Kazumi Ito, Yo-ichi Nabeshima, Okio Hino
    Abstract:

    Hereditary Renal carcinomas in the Eker rat are caused by germline retrotransposon insertion in the tuberous sclerosis-2 (Tsc2) gene. We established previously a transgenic Eker rat model into which was introduced a wild-type Tsc2 gene. The embryonic lethality of mutant homozygotes and Renal Carcinogenesis of heterozygotes were completely suppressed by this transgene (Tg). The function of the Tsc2 product (tuberin) is not fully understood, although several findings have been obtained mainly in vitro. Therefore, to elucidate the functional domains of Tsc2 in vivo, we generated transgenic Eker rats carrying deletion mutants of the Tsc2 gene. A Tg coding for the C-terminal region (amino acids 1425-1755) suppressed Renal Carcinogenesis in the Eker rat and interestingly the degree of this suppression correlated with the level of expression of the Tg. Notably, the product of this Tg lacks the ability to bind to the Tsc1 product (hamartin). Surprisingly, while a Tg lacking the C-terminus of tuberin (amino acids 1-1755) completely suppressed Renal Carcinogenesis, it partially rescued homozygous mutants from embryonic lethality. In conclusion, we have determined the minimal region of tuberin necessary for tumor suppression but the suppressive effect was quantitative. Tuberin could function as a tumor suppressor without binding to hamartin. The requirement of the functional domain(s) of tuberin might differ for prevention of embryonic lethality and for suppression of Renal Carcinogenesis.

Karen Block - One of the best experts on this subject based on the ideXlab platform.

  • Renal Carcinogenesis tumor heterogeneity and reactive oxygen species tactics evolved
    Antioxidants & Redox Signaling, 2016
    Co-Authors: Karthigayan Shanmugasundaram, Karen Block
    Abstract:

    Abstract Significance: The number of kidney cancers is growing 3–5% each year due to unknown etiologies. Intra- and inter-tumor mediators increase oxidative stress and drive tumor heterogeneity. Recent Advances: Technology advancement in state-of-the-art instrumentation and methodologies allows researchers to detect and characterize global landscaping modifications in genes, proteins, and pathophysiology patterns at the single-cell level. Critical Issues: We postulate that the sources of reactive oxygen species (ROS) and their activation within subcellular compartments will change over a timeline of tumor evolvement and contribute to tumor heterogeneity. Therefore, the complexity of intracellular changes within a tumor and ROS-induced tumor heterogeneity coupled to the advancement of detecting these events globally are limited at the level of data collection, organization, and interpretation using software algorithms and bioinformatics. Future Directions: Integrative and collaborative research, combining ...

  • Renal Carcinogenesis, Tumor Heterogeneity, and Reactive Oxygen Species: Tactics Evolved.
    Antioxidants & redox signaling, 2016
    Co-Authors: Karthigayan Shanmugasundaram, Karen Block
    Abstract:

    The number of kidney cancers is growing 3-5% each year due to unknown etiologies. Intra- and inter-tumor mediators increase oxidative stress and drive tumor heterogeneity. Recent Advances: Technology advancement in state-of-the-art instrumentation and methodologies allows researchers to detect and characterize global landscaping modifications in genes, proteins, and pathophysiology patterns at the single-cell level. We postulate that the sources of reactive oxygen species (ROS) and their activation within subcellular compartments will change over a timeline of tumor evolvement and contribute to tumor heterogeneity. Therefore, the complexity of intracellular changes within a tumor and ROS-induced tumor heterogeneity coupled to the advancement of detecting these events globally are limited at the level of data collection, organization, and interpretation using software algorithms and bioinformatics. Integrative and collaborative research, combining the power of numbers with careful experimental design, protocol development, and data interpretation, will translate cancer biology and therapeutics to a heightened level or leave the abundant raw data as stagnant and underutilized. Antioxid. Redox Signal. 25, 685-701.