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Inhibition of DNA primase by sphingosine and its analogues parallels with their growth suppression of cultured human leukemic cells
Author(s) -
TamiyaKoizumi Keiko,
Murate Takashi,
Suzuki Motoshi,
Simbulan Cynthia Marie G.,
Nakagawa Masako,
Takemura Masaharu,
Furuta Keigo,
Izuta Shunji,
Yoshida Shonen
Publication year - 1997
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1080/15216549700202271
Subject(s) - sphingosine , primase , dna , microbiology and biotechnology , parallels , chemistry , biology , biochemistry , gene , reverse transcriptase , rna , receptor , mechanical engineering , engineering
Sphingosine is a potent inhibitor of a mammalian DNA primase in vitro (Simbulan et al., Biochemistry 33, 9007‐9012, 1994). Here we measured the inhibition of DNA primase in vitro by 9 sphingosine‐analogues with respect to RNA primer synthesis and DNA primase‐dependent DNA synthesis, and their potencies of inhibition in vitro were compared with their in vivo effects on human leukemic cells. Sphingosine, phytosphingosine and N, N‐dimethylsphingosine strongly inhibited the activity of purified calf thymus DNA primase, and also inhibited the growth of human leukemic cell line HL‐60, exerting strong cytotoxicity. Dihydrosphingosine and cis‐sphingosine, which showed more subtle inhibition of DNA primase in vitro, moderately inhibited the cell growth in vivo and caused cell death. In contrast, N‐acyl‐, N‐octyl‐, and N‐acetylsphingosine (ceramides) showing little inhibition of DNA primase suppressed cell growth only slightly. HL 60 cell was arrested at Go/G1 phase by exogenously added sphingosine. From these results, it is suggested that DNA primase is one of targets of sphingosine, an effector molecule in apoptosis.