Japanese Foundation For Cancer Research Research Articles

Smad3 Induces Chondrogenesis through the Activation of SOX9 via CREB-binding Protein/p300 Recruitment

The transcriptional activation by SRY-type high mobility group box 9 (SOX9) and the transforming growth factor beta (TGF-beta) signals are necessary for chondrogenic differentiation. We have previously shown that CREB-binding protein (CBP/p300) act as an important SOX9 co-activator during chondrogenesis. In the present study, we investigated the relationship between TGF-beta-dependent Smad2/3 signaling pathways and the SOX9-CBP/p300 transcriptional complex at the early stage of chondrogenesis. Overexpressed Smad3 strongly induced the primary chondrogenesis of human mesenchymal stem cells. In addition, Smad3 enhanced the transcriptional activity of SOX9 and the expression of alpha1(II) collagen gene (COL2A1), and small interference RNA against Smad3 (si-Smad3) inhibited them. We observed that Smad2/3 associated with Sox9 in a TGF-beta-dependent manner and formed the transcriptional complexes with SOX9 on the enhancer region of COL2A1. Interestingly, the association between Sox9 and CBP/p300 was increased by Smad3 overexpression and was suppressed by si-Smad3. Our findings indicate that Smad3 has a stronger potential to stimulate the SOX9-dependent transcriptional activity by modulating the interaction between SOX9 and CBP/p300, rather than Smad2. This study suggests that the Smad3 pathway presents a key role for the SOX9-dependent transcriptional activation in primary chondrogenesis.

Type I Transforming Growth Factor β Receptor Binds to and Activates Phosphatidylinositol 3-Kinase

We have examined the interaction of transforming growth factor (TGF)beta receptors with phosphatidylinositol 3-(PI3) kinase in epithelial cells. In COS7 cells, treatment with TGFbeta increased PI3 kinase activity as measured by the ability of p85-associated immune complexes to phosphorylate inositides in vitro. Both type I and type II TGFbeta receptors (TbetaR) associated with p85, but the association of TbetaRII appeared to be constitutive. The interaction of TbetaRI with p85 was induced by treatment with TGFbeta. The receptor association with PI3 kinase was not direct as (35)S-labeled rabbit reticulocyte p85 did not couple with fusion proteins containing type I and type II receptors. A kinase-dead, dominant-negative mutant of TbetaRII blocked ligand-induced p85-TbetaRI association and PI3 kinase activity. In TbetaRI-null R1B cells, TGFbeta did not stimulate PI3 kinase activity. This stimulation was restored upon reconstitution of TbetaRI by transfection. In R1B and NMuMG epithelial cells, overexpression of a dominant active mutant form of TbetaRI markedly enhanced ligand-independent PI3 kinase activity, which was blocked by the addition of the TbetaRI kinase inhibitor LY580276, suggesting a causal link between TbetaRI function and PI3 kinase. Overexpressed Smad7 also prevented ligand-induced PI3 kinase activity. Taken together, these data suggest that 1) TGFbeta receptors can indirectly associate with p85, 2) both receptors are required for ligand-induced PI3 kinase activation, and 3) the activated TbetaRI serine-threonine kinase can potently induce PI3 kinase activity.

Candicanoside A, a Novel Cytotoxic Rearranged Cholestane Glycoside from Galtonia candicans

A novel cholestane diglycoside, named candicanoside A (1), was isolated from the bulbs of Galtonia candicans by monitoring the cytotoxic activity on HL-60 leukemia cells. Candicanoside A (1) is very unique in structure, having two epoxy functionalities in its rearranged cholestane skeleton, and showed differential cytotoxicity in the Japanese Foundation for Cancer Research 38 cell-line assay.

Regulation of c-Myc through Phosphorylation at Ser-62 and Ser-71 by c-Jun N-Terminal Kinase

The expression of c-myc promotes cell proliferation and also sensitizes cells to various extracellular apoptotic stimuli. However, signal pathways regulating the function of Myc proteins during apoptosis are unknown. c-Jun N-terminal kinase (JNK) is activated by various apoptotic stimuli, but neither the target molecule(s) or the action of JNK has been identified in Myc-mediated apoptosis. Here, we found that JNK selectively interacted with, and phosphorylated, c-Myc at Ser-62 and Ser-71 as confirmed with phospho-c-Myc-specific antibodies. Interestingly, dominant negative mutant JNK(APF) impaired the c-Myc-dependent apoptosis, but not mutated c-Myc (S62A/S71A)-dependent apoptosis triggered by UV irradiation. Furthermore, c-Myc (S62A/S71A)-expressing NIH3T3 cells were not sensitized like wild type c-Myc-expressing NIH3T3 cells to JNK-activating apoptotic stimuli, such as UV and Taxol. These results indicate that the JNK pathway is selectively involved in the c-Myc-mediated apoptosis and that the apoptotic function of c-Myc is directly regulated by JNK pathway through phosphorylation at Ser-62 and Ser-71.

Author reply

We thank Dr. Rayson for expressing interest in the concept of Tenju-gann (pronounced “ten-JEW-gan”) and welcome the opportunity to respond to his comments. Dr. Rayson suggests that the concept of Tenju-gann deserves broader application to diseases among the young and the middle-aged, because the vast majority of advanced solid cancers in these age groups are refractory to therapy. It is naturally very conceivable that the Tenju-gann mind-set might be of great help in reconciling patients and family members to terminal disease, regardless of age, and assist in treatment decisions to allow a “peaceful death with minimal suffering.” We should make every effort to minimize a cancer patient's physical, psychologic, and social burdens. The more widespread development of caring and affordable hospice organizations is urgently needed, and emphasis on palliative care is essential. In these matters, we completely agree with Dr. Rayson. However, whereas the mind-set of Tenju-gann applies to all age groups, the concept as defined can be applied only to those in old age. We would like to explain our thoughts further to clarify a different nuance of the issue. This will be done first from a Japanese perspective and then from a wider perspective. Tenju in Japanese means “healthy, long life,” which is, in traditional Japanese thought, given by heaven to every person at birth. With this concept as the background, we can celebrate when a person has experienced Tenju without encountering or having to deal with serious diseases or accidents. Within the boundaries of this term, a line should be drawn between mere fatalism and the Tenju concept. Most importantly, care should be taken that the Tenju-gann concept not be exploited by therapeutic nihilists. In Japan, in recent years, a book entitled Patients, Don't Fight Against Your Cancer!, written by a radiologist, became particularly popular. The author correctly pointed out the problematic attitude of some surgeons and medical oncologists who perform aggressive treatments in the simplistic subjective belief that those treatments are beneficial, without either objective proof or concern about the patient's quality of life. However, the strong and to some extent inaccurate statements expressed in the book, combined with repeated indiscriminate coverage in the press, has caused a worrisome nihilism among people in their attitudes toward therapy. A tendency now exists among some cancer patients to avoid not only appropriate medical treatments, but also even health checks for early detection of cancer. The backlash clearly has had negative consequences for many cancer patients and for Japanese society in general. Many people feel that cancers, including those occurring in patients of young age, are inevitable. However, there have been many situations in which various types of cancer became preventable and stopped occurring. Others are becoming preventable and declining in their occurrence. Examples of both are occupational cancers, gastric carcinomas, hepatocellular carcinomas after hepatitis B or C virus infection, and squamous cell carcinomas in smokers. Thus, we should be generally optimistic about preventing, or at least delaying, the onset of cancer. Possible cancer development in people with hereditary predisposition could also be eventually avoided or lessened by sophisticated genetic counseling or improved treatment in earlier phases of the disease. Moreover, advanced techniques for diagnosing cancers at an early stage and improved accessibility to those techniques should significantly improve the rate of permanent cure. Subjects treated successfully for primary cancers could develop second and third primary cancers, but recurrence could be well managed. It is no longer rare to see complete cure in cases of multiple cancers. According to Buddhist teaching, heaven gave a life span of about 120 years to humans. L. A. Loeb calculated that prostate carcinoma would develop at the late age of 130 years if the mutation rate could be diminished to half the current rate. Of course, this provides a reason for general optimism, but it needs to be supported by efficacy and progress in cancer prevention as well as improved early diagnosis and treatment. Within the broadest definition of “treatment,” we include mental and psychologic treatment in a manner that allows us to reach the goal of Tenju-gann. Tomoyuki Kitagawa M.D.*, Takashi Sugimura M.D. , * The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo, Japan, National Cancer Center, Tokyo, Japan

Author reply

We thank Dr. Rayson for expressing interest in the concept of Tenju-gann (pronounced “ten-JEW-gan”) and welcome the opportunity to respond to his comments. Dr. Rayson suggests that the concept of Tenju-gann deserves broader application to diseases among the young and the middle-aged, because the vast majority of advanced solid cancers in these age groups are refractory to therapy. It is naturally very conceivable that the Tenju-gann mind-set might be of great help in reconciling patients and family members to terminal disease, regardless of age, and assist in treatment decisions to allow a “peaceful death with minimal suffering.” We should make every effort to minimize a cancer patient's physical, psychologic, and social burdens. The more widespread development of caring and affordable hospice organizations is urgently needed, and emphasis on palliative care is essential. In these matters, we completely agree with Dr. Rayson. However, whereas the mind-set of Tenju-gann applies to all age groups, the concept as defined can be applied only to those in old age. We would like to explain our thoughts further to clarify a different nuance of the issue. This will be done first from a Japanese perspective and then from a wider perspective. Tenju in Japanese means “healthy, long life,” which is, in traditional Japanese thought, given by heaven to every person at birth. With this concept as the background, we can celebrate when a person has experienced Tenju without encountering or having to deal with serious diseases or accidents. Within the boundaries of this term, a line should be drawn between mere fatalism and the Tenju concept. Most importantly, care should be taken that the Tenju-gann concept not be exploited by therapeutic nihilists. In Japan, in recent years, a book entitled Patients, Don't Fight Against Your Cancer!, written by a radiologist, became particularly popular. The author correctly pointed out the problematic attitude of some surgeons and medical oncologists who perform aggressive treatments in the simplistic subjective belief that those treatments are beneficial, without either objective proof or concern about the patient's quality of life. However, the strong and to some extent inaccurate statements expressed in the book, combined with repeated indiscriminate coverage in the press, has caused a worrisome nihilism among people in their attitudes toward therapy. A tendency now exists among some cancer patients to avoid not only appropriate medical treatments, but also even health checks for early detection of cancer. The backlash clearly has had negative consequences for many cancer patients and for Japanese society in general. Many people feel that cancers, including those occurring in patients of young age, are inevitable. However, there have been many situations in which various types of cancer became preventable and stopped occurring. Others are becoming preventable and declining in their occurrence. Examples of both are occupational cancers, gastric carcinomas, hepatocellular carcinomas after hepatitis B or C virus infection, and squamous cell carcinomas in smokers. Thus, we should be generally optimistic about preventing, or at least delaying, the onset of cancer. Possible cancer development in people with hereditary predisposition could also be eventually avoided or lessened by sophisticated genetic counseling or improved treatment in earlier phases of the disease. Moreover, advanced techniques for diagnosing cancers at an early stage and improved accessibility to those techniques should significantly improve the rate of permanent cure. Subjects treated successfully for primary cancers could develop second and third primary cancers, but recurrence could be well managed. It is no longer rare to see complete cure in cases of multiple cancers. According to Buddhist teaching, heaven gave a life span of about 120 years to humans. L. A. Loeb calculated that prostate carcinoma would develop at the late age of 130 years if the mutation rate could be diminished to half the current rate. Of course, this provides a reason for general optimism, but it needs to be supported by efficacy and progress in cancer prevention as well as improved early diagnosis and treatment. Within the broadest definition of “treatment,” we include mental and psychologic treatment in a manner that allows us to reach the goal of Tenju-gann. Tomoyuki Kitagawa M.D.*, Takashi Sugimura M.D. , * The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo, Japan, National Cancer Center, Tokyo, Japan

In vivo ESR observation of mice inoculated with subclones of a colon carcinoma cell line: [formula omitted] Emiko SAKABE1, Takao Yamori2, Hideo Utsumi1. 1:Graduate School of Pharmaceutical Sciences, Kyushu University 2:Japanese Foundation for Cancer Research

In vivo ESR observation of mice inoculated with subclones of a colon carcinoma cell line: [formula omitted] Emiko SAKABE1, Takao Yamori2, Hideo Utsumi1. 1:Graduate School of Pharmaceutical Sciences, Kyushu University 2:Japanese Foundation for Cancer Research

Bone morphogenetic protein 2 acts synergistically with transforming growth factor beta 3 in endothelial-mesenchymal cell transformation during chick heart development.

Annals of the New York Academy of SciencesVolume 857, Issue 1 p. 276-278 Bone Morphogenetic Protein 2 Acts Synergistically with Transforming Growth Factor β3 in Endothelial-Mesenchymal Cell Transformation during Chick Heart Development TOSHIYUKI YAMAGISHI, Corresponding Author TOSHIYUKI YAMAGISHI Department of Anatomy, Saitama Medical School, Saitama, 350-0495 Japan Address for communication: Toshiyuki Yamagishi, Department of Anatomy, Saitama Medical School, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495 Japan. Phone: +81-492-76-1148; fax: +81-492-95-8026; e-mail: [email protected]Search for more papers by this authorYUJI NAKAJIMA, YUJI NAKAJIMA Department of Anatomy, Saitama Medical School, Saitama, 350-0495 JapanSearch for more papers by this authorT. KUBER SAMPATH, T. KUBER SAMPATH Creative Bio Molecules, Inc., Hopkinton, Massachusetts 01748, USASearch for more papers by this authorKOHEI MIYAZONO, KOHEI MIYAZONO Department of Biochemistry, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, 170-8455 JapanSearch for more papers by this authorHIROAKI NAKAMURA, HIROAKI NAKAMURA Department of Anatomy, Saitama Medical School, Saitama, 350-0495 JapanSearch for more papers by this author TOSHIYUKI YAMAGISHI, Corresponding Author TOSHIYUKI YAMAGISHI Department of Anatomy, Saitama Medical School, Saitama, 350-0495 Japan Address for communication: Toshiyuki Yamagishi, Department of Anatomy, Saitama Medical School, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495 Japan. Phone: +81-492-76-1148; fax: +81-492-95-8026; e-mail: [email protected]Search for more papers by this authorYUJI NAKAJIMA, YUJI NAKAJIMA Department of Anatomy, Saitama Medical School, Saitama, 350-0495 JapanSearch for more papers by this authorT. KUBER SAMPATH, T. KUBER SAMPATH Creative Bio Molecules, Inc., Hopkinton, Massachusetts 01748, USASearch for more papers by this authorKOHEI MIYAZONO, KOHEI MIYAZONO Department of Biochemistry, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, 170-8455 JapanSearch for more papers by this authorHIROAKI NAKAMURA, HIROAKI NAKAMURA Department of Anatomy, Saitama Medical School, Saitama, 350-0495 JapanSearch for more papers by this author First published: 07 February 2006 https://doi.org/10.1111/j.1749-6632.1998.tb10131.xCitations: 5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume857, Issue1MORPHOGENESIS: CELLULAR INTERACTIONSOctober 1998Pages 276-278 RelatedInformation

Enhancement of reversing effect of PSC 833 and cyclosporin A on multidrug resistance by anti-P-glycoprotein monoclonal antibody MRK-16

Institute of Molecular and Cellular Biosdences, University of Tokyo, Tokyo 113, Japan. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Sandoz Pharmaceuticals Ltd, Tokyo, Japan.

Potency of cremophor EL to reverse multidrug resistance

Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan. Tsukuba Research Institute, Sandoz Pharmaceuticals Ltd, Ibaraki 300–33, Japan.

Responsiveness of human lung cancer/nude mouse to antitumor agents in a model using clinically equivalent doses : Tashiro T, Inaba M, Kobayashi T et al. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Toshima-ku, Tokyo 170. Cancer Chemother Pharmacol 1989;24:187-92

Responsiveness of human lung cancer/nude mouse to antitumor agents in a model using clinically equivalent doses : Tashiro T, Inaba M, Kobayashi T et al. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Toshima-ku, Tokyo 170. Cancer Chemother Pharmacol 1989;24:187-92

4778756 DNA complementary to RNA of human leukemia virus: Mitsuaki Yoshida, Haruo Sugano, Tokyo, Japan assigned to Juridical Foundation Japanese Foundation for Cancer Research

4778756 DNA complementary to RNA of human leukemia virus: Mitsuaki Yoshida, Haruo Sugano, Tokyo, Japan assigned to Juridical Foundation Japanese Foundation for Cancer Research

4738931 Human interferon-beta gene: Haruo Sugano, Tadatsugu Taniguchi, Shigeo Ono, Tokyo, Japan assigned to Juridical Foundation Japanese Foundation for Cancer Research

4738931 Human interferon-beta gene: Haruo Sugano, Tadatsugu Taniguchi, Shigeo Ono, Tokyo, Japan assigned to Juridical Foundation Japanese Foundation for Cancer Research

Syntheses of 5-Fluorouracil-Terminated Monomethqxypqly(Ethylene Glycol)S, Their Hydrolysis Behavior, and Their Antitumor Activities

Abstract The covalent attachments of 5-fluorouracil (5FU) units to poly(ethylene glycol) monomethoxy ether (MeO-PEG) attached through ester, amide, and ether bonds were carried out; three types of linkages were obtained through which 5FU units were attached to MeO-PEG. For the investigation of the release of the 5FU units, the homogeneous hydrolysis was investigated in vitro in the presence and absence of enzymes. Although the rate of release of l-β-carboxyethyl-5FU or 1-β-hydroxyethyl-5FU from the compounds was fast, the release of 5FU itself was slow. In addition, the antitumor activity of these three types of MeO-PEG-bound 5FU unit was tested in vivo by preliminary screening by the National Cancer Institute or by the Japanese Foundation for Cancer Research.

Structure and Function of Chromatin

Although definitive information on the structure and function of chromatin has not yet been obtained, current work leads us to predict that in the very near future the properties of chromatin and their molecular basis will be understood. It is our hope that this special issue, which details recent advances in the studies of chromatin structure, conformation of intracellular DNA, and gene expression, will be helpful to those now pursuing that goal and will stimulate others to participate in this challenging and promissing endeavor.In this special issue, the following articles are included.(1) Iwai, K. (Institute of Endocrinology, Gumma University).The past and future of chromatin research.(2) Fukada M. (Department of Microbiology, Aichi Medical University).Higher order structure of biological by active DNA in Fukaryotes.(3) Muramatsu, M. (Department of Biochemistry, Cancer Institute, Japanese Foundation for Cancer Research).Organization of Eukaryotic Genes and Splicing.(4) Oba, Y. (Faculty of Pharmaceutical Sciences Kanazawa University).Structure and function of active chromatin.(5) Nakamura, H., Kano, Y., Ishii, S., Miyashita, T., Nagata, A., and F. Imamoto, (Research Institute for Microbial Diseases, Osaka University).Structure and function of prokaryotic nucleoids.(6) Oda, T. (Department of Biochemistry, Cancer Institute, Okayama University Medical School).Structure and function of SV40 chromatin.

Fundamental studies and clinical experiences on the Lu 177 therapy : Hisao Yamashita, Sadanori Igari and Yu Iino, Radiology Department, the Japanese Foundation for Cancer Research

Fundamental studies and clinical experiences on the Lu 177 therapy : Hisao Yamashita, Sadanori Igari and Yu Iino, Radiology Department, the Japanese Foundation for Cancer Research

Navy Consultants' April, 1957, Trip to U. S. Armed Forces Hospitals in the Far East

In the last two weeks of April of this year, 12 naval medical consultants,* including 6 Naval Reserve medical officers on temporary active duty, presented a group of formal papers, made ward rounds, and consulted with the medical officers at the Tripler Army Hospital in Honolulu, the U. S. Naval Hospital in Yokosuka, Japan, and the U. S. Naval Hospital on Guam. In addition, they visited the University of Tokyo Medical School and Hospital, the Cancer Institute of the Japanese Foundation for Cancer Research, the Medical Institute of the Sasaki Foundation in Tokyo, and the Surgical Clinic of Prof. Komei Nakayama at the Hospital of Chiba University, Japan. The consultants were impressed and pleased by the residency- and intern-training program of the U. S. armed forces hospitals visited, the excellent care that patients were receiving, and the efforts that were being made to carry out investigative work, both clinical and