Interleukin 4 regulates G1 cell cycle progression in gastric carcinoma cells.
We have previously reported that interleukin 4 (IL-4) inhibits the growth of human gastric carcinoma cells. To investigate the mechanism for this inhibition we analyzed the effect of IL-4 on cell cycle progression of the IL-4-sensitive gastric carcinoma cell line, HTB-135. IL-4 significantly inhibited cell cycle G1-S-phase progression. To assess the postreceptor molecular events that transduced the negative-growth signals by IL-4, we analyzed the expression of cell cycle nuclear-regulating factors such as retinoblastoma gene product (Rbp), c-myc, c-myc protein (c-mycp), and cyclin D1 expression which are known to be regulators of G1-S-phase transition. IL-4 was found to induce an unphosphorylated form of Rbp within 24 h and significantly reduce the phosphorylated form at 48 h. The transition of Rbp to a hypophosphorylated form concurs with the decrease in c-myc gene expression and c-mycp. In addition, we demonstrated that IL-4 down-regulated p34cdc2, a kinase associated with Rbp phosphorylation and cyclin D1. Cyclin D1, considered as a critical nuclear regulatory factor of G0-G1 to S-phase transition was down-regulated 24 and 48 h post-IL-4 treatment as well. These studies suggest that IL-4 inhibits gastric cell proliferation by blocking cell cycle progression by down-regulating several key G0-G1 cell cycle nuclear-regulating factors.
Morisaki
T
T
John Wayne Cancer Institute, Santa Monica, California 90404.
Uchiyama
A
A
Yuzuki
D
D
Essner
R
R
Morton
D L
DL
Hoon
D S
DS
D000230:Adenocarcinoma / Q000473:pathology*; D016203:CDC2 Protein Kinase / Q000032:analysis; D016213:Cyclins / Q000032:analysis; D016193:G1 Phase / Q000187:drug effects*; D016259:Genes, myc; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000032:analysis; D013274:Stomach Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured
D016213:Cyclins; D016160:Retinoblastoma Protein; D015847:Interleukin-4; D016203:CDC2 Protein Kinase