Transcriptional switch by activating transcription factor 2-derived peptide sensitizes melanoma cells to apoptosis and inhibits their tumorigenicity.

Abstract

The notorious resistance of melanoma cells to drug treatment can be overcome by expression of a 50-aa peptide derived from activating transcription factor 2 (ATF2(50-100)). Here we demonstrate that ATF2(50-100) induced apoptosis by sequestering ATF2 to the cytoplasm, thereby inhibiting its transcriptional activities. Furthermore, ATF2(50-100) binds to c-Jun N-terminal kinase (JNK) and increases its activity. Mutation within ATF2(50-100) that impairs association with JNK and the inhibition of JNK or c-Jun expression by RNA interference (RNAi) reduces the degree of ATF2(50-100)-induced apoptosis. In contrast, TAM67, a dominant negative of the Jun family of transcription factors, or JunD RNAi attenuates sensitization of melanoma cells expressing ATF2(50-100) to apoptosis after treatment with anisomycin, which is used as a model drug. Mutations within the JNK binding region of ATF2(50-100) or expression of TAM67 or JunD RNAi attenuates inhibition of melanoma's tumorigenicity by ATF2(50-100). We conclude that inhibition of ATF2 in concert with increased JNK/Jun and JunD activities is central for the sensitization of melanoma cells to apoptosis and inhibition of their tumorigenicity.

• Authors: Anindita Bhoumik, Nic Jones, Ze'ev Ronai
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 101 Issue 12 Pg. 4222-7 (Mar 23 2004) ISSN: 0027-8424 [Print] United States
• PMID: 15010535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ATF2 protein, human
• Activating Transcription Factor 2
• Atf2 protein, mouse
• Cyclic AMP Response Element-Binding Protein
• Peptides
• Proto-Oncogene Proteins c-jun
• Transcription Factors
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases

Topics

• Activating Transcription Factor 2
• Animals
• Apoptosis (physiology)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Cytoplasm (metabolism)
• Humans
• JNK Mitogen-Activated Protein Kinases
• Melanoma (metabolism)
• Mice
• Mitogen-Activated Protein Kinases (genetics, metabolism)
• Mutation
• Peptides (metabolism)
• Proto-Oncogene Proteins c-jun (metabolism)
• Transcription Factors (metabolism)