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Distinct regulation of p53 and p73 activity by adenovirus E1A, E1B, and E4orf6 proteins
W T Steegenga1, A Shvarts, N Riteco
1Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, Utrecht University, 3508 TA Utrecht, The Netherlands. W.T.Steegenga@med.uu.nl
Abstract:
Multiple adenovirus (Ad) early proteins have been shown to inhibit transcription activation by p53 and thereby to alter its normal biological functioning. Since these Ad proteins affect the activity of p53 via different mechanisms, we examined whether this inhibition is target gene specific. In addition, we analyzed whether the same Ad early proteins have a comparable effect on transcription activation by the recently identified p53 homologue p73. Our results show that the large E1B proteins very efficiently inhibited the activity of p53 on the Bax, p21(Waf1), cyclin G, and MDM2 reporter constructs but had no effect on the activation of the same reporter constructs by p73, with the exception of some inhibition of the Bax promoter by Ad12 E1B. The repressive effect of the E1A proteins on p53 activity is less than that seen with the large E1B proteins, but the E1A proteins inhibit the activity of both p53 and p73. We could not detect significant inhibition of p53 functions by E4orf6, but a clear repression of the transcription activation by p73 by this Ad early protein was observed. In addition, we found that stable expression of the Ad5 E1A and that of the E1B protein both caused increased p73 protein expression. The large E1B and the E4orf6 proteins together do not target the p73 protein for rapid degradation after adenoviral infection, as has previously been found for the p53 protein, probably because the large E1B protein does not interact with p73. Our results suggest that the p53 and p73 proteins are both inactivated after Ad infection and transformation but via distinct mechanisms.
Insights
Adenovirus (Ad) early proteins inactivate tumor suppressors p53 and p73. While large E1B proteins inhibit p53, they spare p73, revealing distinct inactivation mechanisms crucial for understanding Ad infection.
Area of Science:
- Molecular Biology
- Virology
- Cancer Research
Background:
- Adenovirus (Ad) early proteins are known to interfere with the function of the tumor suppressor p53.
- The p53 homologue, p73, is a recently identified protein with similar functions.
- Understanding how Ad proteins affect p53 and p73 is critical for comprehending viral oncogenesis and cellular responses.
Purpose of the Study:
- To investigate whether adenovirus early proteins' inhibition of p53 is target gene-specific.
- To determine if the same Ad early proteins affect the transcriptional activity of p73.
- To elucidate the distinct mechanisms by which Ad infection inactivates p53 and p73.
Main Methods:
- Reporter construct assays were used to measure the transcriptional activity of p53 and p73.
- The effects of Ad early proteins (E1A, E1B, E4orf6) on p53 and p73 activity were assessed.
- Protein expression levels and degradation pathways were analyzed following Ad infection.
Main Results:
- Large E1B proteins strongly inhibited p53 but had minimal effect on p73, except for Ad12 E1B on the Bax promoter.
- E1A proteins repressed both p53 and p73 activity, with a lesser effect than E1B on p53.
- E4orf6 inhibited p73 transcription activation but not p53; Ad5 E1A and E1B increased p73 expression, and E1B/E4orf6 did not target p73 for degradation.
Conclusions:
- Adenovirus early proteins inactivate both p53 and p73, but through distinct mechanisms.
- The differential effects of Ad proteins on p53 and p73 highlight unique viral strategies for subverting host cell functions.
- These findings contribute to understanding how adenoviruses manipulate cellular pathways during infection and transformation.