간암치료신약개발 및 이의 제제화 연구

이현숙; 허윤실; 이영호; 김민재; 김학대; 윤영대; 문홍모

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자료유형: 학술대회자료

저자정보: 이현숙 ([재]목암생명공학연구소 생물정보전달연구실) 허윤실 ([재]목암생명공학연구소 생물정보전달연구실) 이영호 ([재]목암생명공학연구소 생물정보전달연구실) 김민재 ([재]목암생명공학연구소 생물정보전달연구실) 김학대 ([재]목암생명공학연구소 생물정보전달연구실) 윤영대 ([재]목암생명공학연구소 생물정보전달연구실) 문홍모 ([재]목암생명공학연구소 생물정보전달연구실)

저널정보: 한국응용약물학회 한국응용약물학회 춘계학술발표논문집 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회

발행연도: 1994.1

수록면: 178 - 178 (1page)

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Hepatitis B Virus (HBV) is a DNA virus with a 3.2kb partially double-stranded genome. The life cycle of the virus involves a reverse transcription of the greater than genome length 3.5kb mRNA. This pegenomic RNA contains all the genetic information encoded by the virus and functions as an intermediate in viral replication. Tumor suppressor p53 has previously been shown to interact with the X-gene product of the HBV, which led us to hypothesize that p53 may act as a negative regulator of HBV replication and the role of the X-gene product is to overcome the p53-mediated restriction. As a first step to prove the above hypothesis, we tested whether p53 represses the propagation of HBV in in vitro replication system. By transient cotransfection of the plasmid containing a complete copy of the HBV genome and/or the plasmid encoding p53, we found that the replication of HBV is specifically blocked by wild-type p53. The levels of HBV DNA, HBs Ag and HBc/e Ag secreted in cell culture media were dramatically reduced upon coexpresion of wild-type p53 but not by the coexpression of the mutants of p53 (G154V and R273L). Furthermore, levels of RNAs originated from HBV genome were repressed more than 10 fold by the cotransfection of the p53 encoding plasmid. These results clearly states that p53 is a nesative regulator of the HBV replication. Next, to addresss the mechanism by which p53 represses the HBV replication, we performed the transient transfection experiments employing the pregenomic/core promoter-CAT(Chloramphenicol Acetyl Transferase) construct as a reporter. Cotransfection of wild-type p53 but not the mutant p53 expression plasmids repressed the CAT activity more than 8 fold. Integrating the above results, we propose that p53 represses the replication of HBV specifically by the down-regulation of the pregenomic/core promoter, which results in the reduced DNA synthesis of HBV. Currently, the mechanism by which HBV overcomes the observed p53-mediated restriction of replication is tinder investigation.

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