SUMMARY REPORTS OF EXCHANGE SCIENTISTS

(1 ) Takashi Tokino
Sapporo Medical University
Cancer Research Institute

SPONSOR AND HOST INSTITUTION:
Dr. Bert Vogelstein, Professor
Howard Hughes Medical Institute
Johns Hopkins Oncology Center
Dates of Visit: October 27 - November 3, 1997

SUMMARY OF ACTIVITIES:
Discussions on the following topics:
(1) Functional analysis of p53 as a transcriptional activator
(2) Novel p53-target genes
We had many research interests in common and I am sure that this program was a valuable experience for us.
Learning the following new methods:
(1) SAGE (Serial Analysis of Gene Expression). SAGE established by Dr. Vogelstein’s lab has a wide variety of uses, both in identifying unknown genes, and in providing useful information about known genes.
(2) Noninvasive method for monitoring patients with TCC (Transitional Cell Carcinoma) of the bladder. This reliable method established by Dr. Sidransky’s lab was based on microsatellite analysis of urine sediment DNA representing a novel and potentially powerful clinical tool for the detection of recurrent bladder cancer.
Informal Seminar in the Johns Hopkins Oncology Center on November 29:
I talked about a novel p53-target gene we recently identified and obtained many helpful suggestions.
Title:
A Novel Brain-Specific p53-Target Gene, BAI I , Containing Thrombospondin Type 1 Repeats Inhibits Experimental Angiogenesis
Summary :
The genetic alteration of p53 is associated with neovascularization during progression of glioma to its more malignant form, glioblastoma. Hence, one or more of the genes transactivated by p53 is likely to function as an angiogenesis inhibitor. We isolated a novel p53-inducible gene that encodes a 1584-amino-acid product containing five thrombospondin type 1 (TSP-type 1) repeats and is specifically expressed in the brain. A recombinant protein corresponding to the TSP-type 1 repeats of this gene product inhibited in vivo neovascularization induced by bFGF in the rat cornea. The expression of this gene, named BAI1 [Brain-Specific Angiogenesis Inhibitor 1], was absent or significantly reduced in eight of nine glioblastoma cell lines, suggesting BAI1 plays a significant role in angiogenesis inhibitor, as a mediator of p53.
We have also identified two novel human genes homologous to BAI1. Like BAI1, these two genes, named BAI2 and BAI3, were specifically expressed in brain, and are likely to be expressed in the same type of cells. However, in spite of similar tissue specificity among the three BAI genes, only BAI1 is transcriptionally regulated by p53. BAI3 expression was absent in two of nine glioblastoma cell lines examined and was significantly reduced in three of the remaining seven. These data suggest that members of this novel gene family may play important roles in suppression of glioblastoma.



(2) Tetsu Akiyama
Department of Oncogene Research
Research Institute for Microbial Diseases
Osaka University

SPONSOR AND HOST INSTITUTION:
Dr. Ichiro Maruyama
The Scripps Research Institute
Molecular Genetics
Dates of Visit: March 2 - 8, 1998

SUMMARY OF ACTIVITIES:
I gave a seminar entitled “The Function of the Colorectal Tumor Suppressor APC.”
Then we learned basic techniques required for the experiments using C. elegans under the direct of Dr. I. N. Maruyama. It has recently been revealed that the Wnt/Wingless signaling pathway plays an important role in P2-EMS signaling in C. elegans. Thus we discussed the function of C. elegans APC in this signaling pathway and decided to continue the collaboration. Dr. Maruyanra is also interested in developing new technologies.
For example, he succeeded to map an epitope determinant of galactin-3 utilizing the bacteriophage lamda surface expression system. He also analyzed the structure and function of the transmembrane segment of the aspartate receptor by cassette mutagenesis and site-specific disulfide cross-linking, and proposed a simple mechanical model for the transmembrane signaling.
We also visited the laboratory of Dr. P. K. Vogt who is working on the function of the viral transforming gene jun. He already isolated target genes for Jun by the subtraction cloning method but cellular transformation was not induced by simply overexpressing these target genes into chicken fibroblast cells. He recently identified a novel oncogene derived from PI3 kinase and revealed that efficient membrane localization due to the fusion with gag is responsible for its transforming activity. He is also trying to isolate novel oncogenes utilizing retroviral expression library, but so far he obtained fos and beta-catenin. Additionally he was working on small molecules which recognize specific DNA or RNA sequences and inhibit transcription or translation, respectively.
I am impressed to find that he is always prepared to adopt new technologies into his research.