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p53-Dependent and -independent functions of the Arf tumor suppressor
C J Sherr1, D Bertwistle, W DEN Besten
1Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Abstract:
The Ink4a-Arf locus encodes two closely wedded tumor suppressor proteins (p16(Ink4a) and p19(Arf)) that inhibit cell proliferation by activating Rb and p53, respectively. With few exceptions, the Arf gene is repressed during mouse embryonic development, thereby helping to limit p53 expression during organogenesis. However, in adult mice, sustained hyperproliferative signals conveyed by somatically activated oncogenes can induce Arf gene expression and trigger a p53 response that eliminates incipient cancer cells. Disruption of this tumor surveillance pathway predisposes to cancer, and inactivation of INK4a- ARF by deletion, silencing, or mutation has been frequently observed in many forms of human cancer. Although it is accepted that much of Arf's tumor-suppressive activity is mediated by p53, more recent genetic evidence has pointed to additional p53- independent functions of Arf, including its ability to inhibit gene expression by a number of other transcription factors. Surprisingly, the enforced expression of Arf in mammalian cells promotes the sumoylation of several Arf-interacting proteins, implying that Arf has an associated catalytic activity. We speculate that transcriptional down-regulation in response to Arf-induced sumoylation may account for Arf's p53-independent functions.
Insights
The Ink4a-Arf locus, encoding tumor suppressors p16(Ink4a) and p19(Arf), is crucial for preventing cancer. Arf
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- The Ink4a-Arf locus produces two tumor suppressor proteins, p16(Ink4a) and p19(Arf), which regulate cell proliferation via Rb and p53 pathways, respectively.
- Arf gene expression is typically repressed during embryonic development but induced by oncogenes in adult mice to eliminate precancerous cells.
- Inactivation of the Ink4a-Arf locus is common in human cancers, highlighting its role in tumor suppression.
Purpose of the Study:
- To investigate the tumor suppressive functions of the Ink4a-Arf locus, particularly the p53-independent roles of Arf.
- To explore the mechanism by which Arf exerts its functions, including its potential catalytic activity and interaction with sumoylation.
Main Methods:
- Analysis of Ink4a-Arf locus function in mouse models.
- Genetic studies to assess the role of p53 in Arf-mediated tumor suppression.
- Biochemical assays to investigate Arf-interacting proteins and sumoylation processes.
Main Results:
- Disruption of the Ink4a-Arf tumor surveillance pathway increases cancer predisposition.
- Evidence suggests Arf possesses p53-independent functions, including inhibition of gene expression via other transcription factors.
- Enforced Arf expression promotes sumoylation of interacting proteins, indicating a possible catalytic activity.
Conclusions:
- Arf's tumor-suppressive activity is partly mediated by p53 but also involves p53-independent mechanisms.
- Arf-induced sumoylation of interacting proteins may lead to transcriptional down-regulation, explaining its p53-independent functions.
- Understanding Arf's multifaceted roles is critical for developing novel cancer therapies.
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