TY - JOUR

T1 - E2F activity is essential for survival of Myc-overexpressing human cancer cells

AU - Santoni-Rugiu, Eric

AU - Duro, Dominique

AU - Farkas, Thomas

AU - Mathiasen, Ida S.

AU - Jäättelä, Marja

AU - Bartek, Jiri

AU - Lukas, Jiri

PY - 2002

Y1 - 2002

N2 - Effective cell cycle completion requires both Myc and E2F activities. However, whether these two activities interact to regulate cell survival remains to be tested. Here we have analysed survival of inducible c-Myc-overexpressing cell lines derived from U2OS human osteosarcoma cells, which carry wild-type pRb and p53 and are deficient for p16 and ARF expression. Induced U2OS-Myc cells neither underwent apoptosis spontaneously nor upon reconstitution of the ARF-p53 axis and/or serum-starvation. However, they died massively when concomitantly exposed to inhibitors of E2F activity, including a constitutively active pRb (RbΔcdk) mutant, p16, a stable p27 (p27T187A) mutant, a dominant-negative (dn) CDK2, or dnDP-1. Similar apoptotic effect was observed upon down-modulation of endogenous E2Fs through overexpression of E2F binding site oligonucleotides in U2OS-Myc cells, upon expression of RbΔcdk or dnDP-1 in the Myc-amplified HL-60 (ARF-; p53-) human leukemia cells, and upon co-transfection of Myc and RbΔcdk in SAOS-2 (ARF+; p53-) human osteosarcoma cells but not in human primary fibroblasts. Consistent with these results, a dnp53 mutant did not abrogate the Myc-induced apoptotic phenotype, which instead strictly depended on caspase-3-like proteases and on Myc transcriptional activity. Our data indicate that in contrast to normal cells, Myc-overexpressing human cancer cells need E2F activity for their survival, regardless of their ARF and p53 status, a notion that may have important implications for antineoplastic treatment strategies.

AB - Effective cell cycle completion requires both Myc and E2F activities. However, whether these two activities interact to regulate cell survival remains to be tested. Here we have analysed survival of inducible c-Myc-overexpressing cell lines derived from U2OS human osteosarcoma cells, which carry wild-type pRb and p53 and are deficient for p16 and ARF expression. Induced U2OS-Myc cells neither underwent apoptosis spontaneously nor upon reconstitution of the ARF-p53 axis and/or serum-starvation. However, they died massively when concomitantly exposed to inhibitors of E2F activity, including a constitutively active pRb (RbΔcdk) mutant, p16, a stable p27 (p27T187A) mutant, a dominant-negative (dn) CDK2, or dnDP-1. Similar apoptotic effect was observed upon down-modulation of endogenous E2Fs through overexpression of E2F binding site oligonucleotides in U2OS-Myc cells, upon expression of RbΔcdk or dnDP-1 in the Myc-amplified HL-60 (ARF-; p53-) human leukemia cells, and upon co-transfection of Myc and RbΔcdk in SAOS-2 (ARF+; p53-) human osteosarcoma cells but not in human primary fibroblasts. Consistent with these results, a dnp53 mutant did not abrogate the Myc-induced apoptotic phenotype, which instead strictly depended on caspase-3-like proteases and on Myc transcriptional activity. Our data indicate that in contrast to normal cells, Myc-overexpressing human cancer cells need E2F activity for their survival, regardless of their ARF and p53 status, a notion that may have important implications for antineoplastic treatment strategies.

KW - E2F

KW - Human cancer cells

KW - Myc

KW - Survival

UR - http://www.scopus.com/inward/record.url?scp=0037136698&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1205828

DO - 10.1038/sj.onc.1205828

M3 - Journal article

C2 - 12226753

AN - SCOPUS:0037136698

VL - 21

SP - 6498

EP - 6509

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 42

ER -