Inhibition of p53-induced apoptosis without affecting expression of p53-regulated genes.
Using DNA microarray and clustering of expressed genes we have analyzed the mechanism of inhibition of wild-type p53-induced apoptosis by the cytokine interleukin 6 (IL-6) and the calcium mobilizer thapsigargin (TG). Clustering analysis of 1,786 genes, the expression level of which changed after activation of wild-type p53 in the absence or presence of IL-6 or TG, showed that these compounds did not cause a general inhibition of the ability of p53 to up-regulate or down-regulate gene expression. Expression of various p53 targets implicated as mediators of p53-induced apoptosis was also not affected by IL-6 or TG. These compounds thus can bypass the effect of wild-type p53 on gene expression and inhibit apoptosis. IL-6 and TG activated different p53-independent pathways of gene expression that include up-regulation of antiapoptotic genes. IL-6 and TG also activated different differentiation-associated genes. The ability of compounds such as cytokines and calcium mobilizers to inhibit p53-mediated apoptosis without generally inhibiting gene expression regulated by p53 can facilitate tumor development and tumor resistance to radiation and chemotherapy in cells that retain wild-type p53.
Lotem
Joseph
J
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Gal
Hilah
H
Kama
Rachel
R
Amariglio
Ninette
N
Rechavi
Gideon
G
Domany
Eytan
E
Sachs
Leo
L
Givol
David
D
D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation; D016000:Cluster Analysis; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019284:Thapsigargin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D017931:DNA Primers; D015850:Interleukin-6; D016159:Tumor Suppressor Protein p53; D019284:Thapsigargin