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Transactivation activity of Maf nuclear oncoprotein is modulated by Jun, Fos and small Maf proteins
K Kataoka1, M Noda, M Nishizawa
1Department of Viral Oncology, Cancer Institute, Tokyo, Japan.
Abstract:
The v-maf oncogene encodes a nuclear bZip protein which specifically recognizes relatively long palindromic sequences related to an AP-1 site. In this study, we investigated the relationship of transactivation and transformation activity of Maf. The amino-terminal two thirds of the molecule were dispensable for its DNA-binding activity but conferred its transactivation potential. Transactivation activities of a set of deletion mutants correlated well with their cell transforming abilities. However, a point mutant associated with enhanced oncogenic activity was not more effective in transactivation than the wild type, suggesting that some other function(s) of Maf is also important for its transforming ability. We also examined the effect of other bZip proteins on the transactivation activity of Maf. Three small Maf family proteins (MafK, MafF and MafG), which are missing the transactivation domain of v-Maf, competitively inhibited transactivation by Maf. Co-expression of Jun or Fos also affected the transactivation potential of Maf by forming Maf/Jun or Maf/Fos heterodimers of distinct DNA-binding specificities. In addition to these factors, we noticed the presence of a strong endogenous transactivating activity associated with a sequence related to an NF-E2 site rather than the typical AP-1 site in fibroblast cells. These results indicate that AP-1 site-like cis-regulatory elements of eukaryotic genes are regulated by multiple sets of bZip dimers with different DNA-binding and transactivation properties.
Insights
The v-Maf oncogene
Area of Science:
- Molecular Biology
- Oncology
- Gene Regulation
Background:
- The v-Maf oncogene encodes a nuclear bZip protein.
- v-Maf recognizes specific DNA sequences related to the AP-1 site.
Purpose of the Study:
- Investigate the relationship between transactivation and transformation activity of Maf.
- Examine the influence of other bZip proteins on Maf's transactivation.
Main Methods:
- Deletion mutant analysis of Maf.
- Assessing transactivation and cell transforming abilities.
- Studying interactions with other bZip proteins (MafK, MafF, MafG, Jun, Fos).
Main Results:
- The amino-terminal region of Maf is crucial for transactivation but not DNA binding.
- Transactivation activity correlated with cell transformation, but a hyper-oncogenic mutant showed similar transactivation.
- Other bZip proteins, including small Mafs, Jun, and Fos, modulated Maf's transactivation through competitive inhibition or heterodimer formation.
- Endogenous transactivating activity was observed at NF-E2 related sites in fibroblasts.
Conclusions:
- Maf's transforming ability involves functions beyond simple transactivation.
- AP-1 site-like regulatory elements are controlled by diverse bZip dimers with varied DNA-binding and transactivation properties.
- Multiple bZip proteins contribute to the complex regulation of eukaryotic gene expression.