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Autocrine growth and anchorage independence: two complementing Jun-controlled genetic programs of cellular
H van Dam1, S Huguier, K Kooistra
1Laboratory for Molecular Carcinogenesis, Sylvius Laboratories, University of Leiden, 2300 RA Leiden, The Netherlands.
Genes & Development
|May 30, 1998
Summary
Cellular transformation involves distinct processes. Jun transcription factors, through specific heterodimers, independently control anchorage and growth factor independence, revealing separate genetic programs for cell transformation.
Area of Science:
- Molecular Biology
- Cellular Biology
- Oncology
Background:
- Cellular transformation, a key step in cancer development, is driven by activated growth-regulatory pathways and transcription factors.
- Activating transcription factor (ATF) and Jun dimerization (AP-1) are central to these pathways, influencing gene expression programs.
- The viral Jun protein in chick embryo fibroblasts (CEFs) promotes enhanced growth in agar and low serum, hallmarks of transformation.
Purpose of the Study:
- To dissect the distinct genetic programs underlying Jun-mediated cellular transformation.
- To investigate the roles of specific Jun heterodimer partners (Fos and ATF2 families) in transformation processes.
- To determine if anchorage independence and growth factor independence are separable components of transformation.
Main Methods:
- Construction of Jun bZip mutants with selective dimerization capabilities for Fos or ATF2 family members.
- Introduction of these mutants into CEFs to assess their effects on cellular transformation.
- Analysis of anchorage-independent growth (growth in agar) and growth factor-independent proliferation.
Main Results:
- A Jun mutant selective for Fos family partners induced anchorage-independent growth but not growth factor independence.
- A c-Jun mutant preferring ATF2-like proteins induced growth factor independence but not anchorage-independent growth.
- Coexpression of both selective Jun mutants restored the full transformation phenotype, including both anchorage and growth factor independence.
Conclusions:
- Jun-dependent cell transformation can be resolved into at least two distinct, independent processes: anchorage independence and growth factor independence.
- These two processes are triggered by distinct Jun heterodimers, likely involving different classes of partner proteins (Fos vs. ATF2).
- Each Jun heterodimer class regulates separate genetic programs critical for specific aspects of cellular transformation.