Abstract
We have previously identifed 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 (ATF2Δ1 – 195). MeWo cells that stably express ATF2Δ1 – 195 showed weaker transcriptional activities and an altered pattern of homo/hetero dimers. ATF2Δ1-195 clones exhibited up to tenfold lower resistance to irradiation by either U.V. or X-rays. The degree of resistance to radiation in the ATF2Δ1 – 195-expressing clones could be increased upon transient transfection with ATF2wt, but not with phosphorylation-defective mutant ATF269,71. Similarly, transfection of ATF2wt to WM3211, an early stage human melanoma cells line, increased resistance to radiation. Finally, changes elicited through ATF2Δ1 – 195 also led to reduced drug resistance, as shown for MMC, araC and cis-platinum. 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.
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Ronai, Z., Yang, Ym., Fuchs, S. et al. ATF2 confers radiation resistance to human melanoma cells. Oncogene 16, 523–531 (1998). https://doi.org/10.1038/sj.onc.1201566
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DOI: https://doi.org/10.1038/sj.onc.1201566
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