ATF2 confers radiation resistance to human melanoma cells.
We have previously identified a U.V.-response element (URE; TGACAACA) and its bound proteins, members of the AP1 and ATF transcription factor families, in melanoma cells. Using a mutant form of cylic AMP response element binding (CREB), we found that CREB-associated-URE-bound proteins conferred characteristic melanoma phenotypes, including radiation resistance (Oncogene 12: 2223, 1996). In the present study we sought to determine which of the CREB-associated proteins confers radiation resistance on human melanoma cells. To this end we purified and identified via microsequencing ATF2 as a major URE- bound and CREB-associated protein in MeWo cells--a late stage human melanoma cell line. To determine the contribution of ATF2 to radiation resistance, MeWo cells were transfected with ATF2 cDNA lacking the trans-activation domain (ATF2(delta1-195)). MeWo cells that stably express ATF2(delta1-195) showed weaker transcriptional activities and an altered pattern of homo/hetero dimers. ATF2(delta1-195) clones exhibited up to tenfold lower resistance to irradiation by either U.V. or X-rays. The degree of resistance to radiation in the ATF2(delta1-195)-expressing clones could be increased upon transient transfection with ATF2(wt), but not with phosphorylation-defective mutant ATF2(69,71). Similarly, transfection of ATF2(wt) to WM3211, an early stage human melanoma cells line, increased resistance to radiation. Finally, changes elicited through ATF2(delta1-195) also led to reduced drug resistance, as shown for MMC, araC and cisplatinum. Our results suggest that ATF2 is a regulator of radiation and drug resistance in melanomas, and that tumor targeted ATF2 modulators may be useful sensitizers in the treatment of tumors of this type.
Ronai
Z
Z
The Ruttenberg Cancer Center, Mount Sinai Medical School, New York, NY 10029-6574, USA.
Yang
Y M
YM
Fuchs
S Y
SY
Adler
V
V
Sardana
M
M
Herlyn
M
M
D051698:Activating Transcription Factor 2; D002455:Cell Division / Q000528:radiation effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009367:Neoplasm Staging; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011836:Radiation Tolerance / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; C064255:GAL4 (1-147) protein, S cerevisiae; D009363:Neoplasm Proteins; D009841:Oligonucleotides; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors