AP180의 Phospholipase D 활성억제 motif규명및 기전 연구
- Title
- AP180의 Phospholipase D 활성억제 motif규명및 기전 연구
- Other Titles
- Identification and regulatory mechanism of AP180 motif that inhibits phospholipase D activity: application to the development of enhancer drugs which improve chemotherapeutic efficacy
- Author
- 김형주
- Alternative Author(s)
- Hyoung-Ju Kim
- Advisor(s)
- 권성준
- Issue Date
- 2010-08
- Publisher
- 한양대학교
- Degree
- Doctor
- Abstract
- Identification and regulatory mechanism of AP180 motif
that inhibits phospholipase D activity:
application to the development of enhancer drugs which improve chemotherapeutic efficacy
Kim, Hyoung-Ju
Directed by Prof. Sung Joon Kwon
Department of Surgery, College of Medicine, Graduate School, Hanyang University
Phospholipase D (PLD) hydrolyses phosphatidylcholine to phosphatidic acid (PA) and choline. PLD has two isoforms, PLD1 and PLD2, both isoforms are possible candidates for the development of anticancer drug, since PLDs in several cancer cells act as survival factors against death signal. This study tried to elucidate the precise inhibition mechanisms of PLD1 activity by AP180 in cancer cells. According to previous studies, clathrin assembly proteins such as amphiphysins, synaptojanin, and AP180 can inhibit PLD activity. Among these proteins human AP180 (hAP180) gene was cloned from human cDNA library, and inhibition of phobol-12-myristate 13-acetate (PMA) induced PLD activity was occurred by hAP180 transfection. We have found that motif from 290 to 320 in rat AP180 (rAP180) is essential for both binding of PLD and inhibition of PLD activity. Here we further elucidated the residues in hAP180 which are responsible for the interaction with PLD1 by performing hAP180 and PLD1 (or PLD2) deletion mutant study. From our results, three amino acids (The312 ~Pro314) were shown as a critical region for the inhibition of PLD1 activity. Among them, Ser313 was found to be the most important residue for binding to PLD1 and thus inhibition of PLD1 activity. However these residues in hAP180 were not interacted with hPLD2. Furthermore, second phosphodiesterase domain in PLD1 is important for the interaction with hAP180. These results indicated that Thr312~Pro314 (especially Ser313 as a phosphorylation residue) of hAP180 can regulate hPLD1 activity through binding with the second phosphodiesterase domain of PLD1 but not to PLD2. Taken together, these amino acids sequences are able to be applied to the synthesis of a therapeutic peptidomimetic drug which can inhibit PLD activity, thus PLD-related survival signal in cancer will be under control.
- URI
- https://repository.hanyang.ac.kr/handle/20.500.11754/140925http://hanyang.dcollection.net/common/orgView/200000414646
- Appears in Collections:
- GRADUATE SCHOOL[S](대학원) > MEDICINE(의학과) > Theses (Ph.D.)
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