JWA, a novel signaling molecule, involved in all-trans retinoic acid induced differentiation of HL-60 cells.
JWA (AF070523) was originally identified as a novel all-trans retinoic acid (ATRA) responsible gene in primary human tracheal bronchial epithelial cells. For the notable performance achieved by ATRA in the differentiation induction therapy, we investigated the role of JWA in ATRA-mediated differentiation of the human myeloid leukemia HL-60 cells. We found that concomitant with the progressive cell differentiation, JWA expression was up-regulated by ATRA in a dose- and time-dependent manner. Inhibition of JWA expression by RNA interference partially blocked ATRA-induced differentiation and growth inhibition of HL-60 cells. Pre-treatment of phorbol-12-myristate-13-acetate (TPA), a PKC activator, decreased ATRA-mediated differentiation, companied with the down-regulation of JWA expression. Arsenic trioxide (As(2)O(3), 0.5 microM) enhanced the cellular differentiation induced by 0.01 microM ATRA, but had no noticeable effect on the differentiation induced by 0.1 microM ATRA. Concurrent with the enhancement, JWA expression was up-regulated. All the data suggest that up-regulation of JWA expression is essential for ATRA-induced differentiation of HL-60 cells. And JWA, associated with PKC, is involved in its signal pathways. Ideal therapeutic efficacy with low toxicity may be obtained if low doses of ATRA (0.01 microM) and As(2)O(3) (0.5 microM) are combined. These findings may present a novel mechanism that cellular differentiation and growth inhibition induced by ATRA are mediated at least in part through regulation of JWA expression. JWA may be a novel molecular marker for ATRA-induced HL-60 cell differentiation. ATRA up-regulates JWA expression by stimulating the transcriptional activity of JWA gene promoter.
Huang
Shu
S
Department of Molecular Cell Biology and Toxicology, Jiangsu Provincial Key Laboratory of Human Functional Genomics and Applied Toxicology, School of Public Health, Nanjing Medical University, China.
Shen
Qun
Q
Mao
Wen-Ge
WG
Li
Ai-Ping
AP
Ye
Jian
J
Liu
Qi-Zhan
QZ
Zou
Chang-Ping
CP
Zhou
Jian-Wei
JW
D002454:Cell Differentiation; D002470:Cell Survival; D015536:Down-Regulation; D017930:Genes, Reporter; D018922:HL-60 Cells; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D026901:Membrane Transport Proteins; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D013755:Tetradecanoylphorbol Acetate; D015533:Transcriptional Activation; D014212:Tretinoin / Q000378:metabolism*; D015854:Up-Regulation
C484566:ARL6IP5 protein, human; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D014212:Tretinoin; D013755:Tetradecanoylphorbol Acetate