Restoration of p53 functions protects cells from concanavalin A-induced apoptosis.
A great majority of human cancers encounter disruption of the p53 network. Identification and characterization of molecular components important in both p53-dependent and p53-independent apoptosis might be useful in developing novel therapies. Previously, we reported that concanavalin A (Con A) induced p73-dependent apoptosis of cells lacking functional p53. In the present study, we investigated the mechanism and role of p53 in protection from apoptosis induced by Con A. Treatment with Con A resulted in apoptosis of p53-null ovarian cancer, SKOV3, or Li-Fraumeni syndrome, MDAH041 (041), cells. However, their isogenic pairs, SKP53 and TR9-7, expressing wild-type p53 were much less sensitive and were protected by G(1) arrest. Inhibition of p53 function rendered these cells sensitive to Con A. Con A-induced apoptosis was accompanied by upregulation of forkhead box O1a (FOXO1a) and Bcl-2-interacting mediator (Bim), which were strongly inhibited after p53 expression and rescued after p53 ablation. Moreover, ablation of Bim by short hairpin RNA protected cells from apoptosis. Taken together, our study suggests that Con A induces apoptosis of cells lacking p53 by activating FOXO1a-Bim signaling and that expression of p53 protects these cells by inducing G(1) arrest and by downregulating the expression of both FOXO1a and Bim, identifying a novel cross-talk between FOXO1a and p53 transcription factors.
Amin
A R M Ruhul
AR
Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Thakur
Vijay S
VS
Gupta
Kalpana
K
Jackson
Mark W
MW
Harada
Hisashi
H
Agarwal
Mukesh K
MK
Shin
Dong M
DM
Wald
David N
DN
Agarwal
Munna L
ML
D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D003208:Concanavalin A / Q000494:pharmacology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003208:Concanavalin A