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p53 domains: suppression, transformation, and transactivation
1Department of Microbiology, State University of New York, Stony Brook 11794.
Abstract:
We investigated the suppression, transformation, and transactivation functions of isolated segments of wild-type murine p53. Intact p53, but no segment of p53, inhibited cellular transformation by the activated ras and adenovirus E1A proteins. We conclude that most of p53 is needed for suppression of cellular proliferation. Nevertheless, the transactivating domain of herpesvirus protein VP16 was able to substitute for the N-terminal transactivating domain of p53 in cellular suppression. Thus, unless the interchanged p53 and VP16 acidic segments share additional functions, transactivation is required for suppression by p53. Interestingly, we found that all p53 segments containing amino acids 320-360 enhanced transformation by ras and E1A. This region has been associated with the oligomerization of p53 (Milner et al., 1991; Sturzbecher et al., 1992). Furthermore, no p53 segment lacking amino acids 320-360 transformed cells. Amino acids 320-360, therefore, may account for the major transforming activity of p53. Intact p53 and chimeric VP16-p53 transactivated the CAT gene under control of a p53-specific promoter, while transforming segments of p53 interfered with transactivation by wild-type p53. Our findings argue that transactivation by p53 is required for cellular suppression and that any nontransactivating p53 that retains the capacity to oligomerize with wild-type p53 would have transformation potential.
Insights
The tumor suppressor p53 requires most of its structure for inhibiting cell growth. However, its transactivation function is essential for this suppression, with specific regions promoting transformation.
Area of Science:
- Molecular Biology
- Oncology
- Virology
Background:
- The tumor suppressor protein p53 plays a critical role in preventing cancer.
- Understanding the specific functions of p53 domains is crucial for cancer research.
Purpose of the Study:
- To investigate the distinct functional domains of murine p53, specifically its roles in suppressing cellular transformation, transactivation, and its potential oncogenic activities.
- To determine the relationship between p53's transactivation capability and its tumor-suppressive function.
Main Methods:
- Analysis of isolated segments of wild-type murine p53.
- Assessing the inhibition of cellular transformation induced by activated ras and adenovirus E1A proteins.
- Evaluating the transactivation of a CAT gene using a p53-specific promoter.
- Investigating the role of amino acids 320-360 in p53 function and transformation.
Main Results:
- Intact p53 inhibited cellular transformation, but no single segment could.
- The transactivating domain of herpesvirus protein VP16 could substitute for p53's N-terminal transactivating domain in cellular suppression, suggesting transactivation is required for suppression.
- p53 segments containing amino acids 320-360 enhanced transformation and were essential for the transforming activity of p53.
- Transforming p53 segments interfered with wild-type p53 transactivation.
Conclusions:
- Most of the p53 protein is necessary for suppressing cellular proliferation.
- Transactivation is a required function for p53-mediated cellular suppression.
- The p53 region 320-360 is critical for transformation and may mediate this through oligomerization with wild-type p53, potentially acting as a dominant-negative inhibitor.