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Initial Evaluation of Antibody-conjugates Modified with Viral-derived Peptides for Increasing Cellular Accumulation and Improving Tumor Targeting
Published on: March 8, 2018
The anaphase promoting complex: a critical target for viral proteins and anti-cancer drugs
Destin W Heilman1, Michael R Green, Jose G Teodoro
1Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Abstract:
The study of animal viruses has provided extraordinary insights into cell cycle dynamics and tumor biology. The significance of the p53 and Rb tumor suppressor proteins, for example, was discovered due to their interactions with viral oncogenes. In the past several years, investigations with four viral proteins, human immunodeficiency virus type 1 (HIV-1) vpr, adenovirus E4orf4, chicken anemia virus (CAV) apoptin and human T lymphotropic virus type I (HTLV-I) Tax, have indicated that there are also critical viral targets involved in G2/M control. In particular, recent studies with E4orf4 and apoptin have shown that they induce G2/M arrest by targeting and inhibiting the anaphase-promoting complex/cyclosome (APC/C). Notably, these two viral proteins induce apoptosis selectively in transformed cells in a p53-independent manner; thus pathways affected by these proteins are of significant therapeutic interest. Further investigation of the underlying mechanism of G2/M arrest and subsequent apoptosis induced by viral APC/C inhibitors may shed light on the mechanisms of current cancer therapies and provide the foundation for developing novel therapeutic targets.
Insights
Viral proteins targeting the anaphase-promoting complex/cyclosome (APC/C) induce cell cycle arrest and apoptosis. These findings offer new therapeutic targets for cancer treatment, particularly in p53-independent pathways.
Area of Science:
- Virology
- Cell Biology
- Cancer Biology
Background:
- Animal viruses have historically illuminated fundamental cellular processes, including cell cycle regulation and tumor development.
- The roles of tumor suppressors p53 and Rb were initially uncovered through their interactions with viral oncogenes.
- Recent research highlights viral proteins impacting G2/M cell cycle control, including HIV-1 vpr, adenovirus E4orf4, CAV apoptin, and HTLV-I Tax.
Purpose of the Study:
- To investigate the mechanisms by which viral proteins E4orf4 and apoptin induce G2/M cell cycle arrest.
- To explore the selective induction of apoptosis in transformed cells by these viral proteins.
- To identify potential therapeutic strategies targeting viral-induced cell cycle disruption in cancer.
Main Methods:
- Investigated the interaction of viral proteins E4orf4 and apoptin with cellular targets.
- Analyzed the induction of G2/M cell cycle arrest mediated by these viral proteins.
- Assessed the induction of apoptosis in cancer cells in a p53-independent manner.
Main Results:
- Adenovirus E4orf4 and chicken anemia virus apoptin were shown to inhibit the anaphase-promoting complex/cyclosome (APC/C).
- These viral proteins induce G2/M cell cycle arrest by targeting the APC/C.
- E4orf4 and apoptin selectively trigger apoptosis in transformed cells, independent of p53 function.
Conclusions:
- Viral proteins targeting the APC/C represent a significant mechanism for inducing G2/M arrest and apoptosis.
- The p53-independent induction of apoptosis by these viral proteins presents promising therapeutic avenues for cancer treatment.
- Understanding these viral pathways can inform the development of novel anti-cancer therapies and enhance existing treatment strategies.
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