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Arf induces p53-dependent and -independent antiproliferative genes
Mei-Ling Kuo1, Eric J Duncavage, Rose Mathew
1Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Abstract:
The tumor suppressor p19(Arf) (p14(ARF) in humans), encoded by the Ink4a/Arf locus, is mutated, deleted, or silenced in many forms of cancer. p19(Arf) induces growth arrest by antagonizing the activity of the p53-negative regulator, Mdm2, thereby inducing a p53 transcriptional response. p19(Arf) can also inhibit cell cycle progression of mouse embryo fibroblasts lacking Cip1 or lacking both Mdm2 and p53, although in the absence of p53, arrest occurs more slowly. Profiling with high-density oligonucleotide GeneChips and cDNA microarrays was used to interrogate mouse genes, the expression of which was induced or suppressed by a conditionally regulated Arf gene. Cluster analysis of temporal gene expression patterns and validation of the results by RNA analysis identified Arf-responsive genes whose induction was both p53-dependent and -independent. The latter included four members of the B-cell translocation gene family (Btg1, Btg2, Btg3, and Tob1) that were demonstrated to inhibit cell proliferation in primary mouse embryo fibroblasts expressing or lacking functional p53. Together, the results indicate that p19(Arf) induces a broad spectrum of proteins that likely act in concert to arrest cell proliferation.
Insights
The tumor suppressor p19(Arf) halts cancer cell growth by regulating p53. Researchers identified p53-dependent and independent genes, including Btg family members, that contribute to this cell proliferation arrest.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The tumor suppressor p19(Arf) (p14(ARF) in humans) is crucial for preventing cancer and is often inactivated in tumors.
- p19(Arf) antagonizes Mdm2, a negative regulator of p53, leading to p53-mediated growth arrest.
Purpose of the Study:
- To identify genes regulated by p19(Arf) in a p53-dependent and -independent manner.
- To understand the broader molecular mechanisms by which p19(Arf) inhibits cell proliferation.
Main Methods:
- Utilized high-density oligonucleotide GeneChips and cDNA microarrays for global gene expression profiling in mouse models.
- Employed cluster analysis for temporal gene expression patterns and RNA analysis for validation.
- Assessed the role of identified genes in cell proliferation using primary mouse embryo fibroblasts.
Main Results:
- Identified a set of Arf-responsive genes, including those induced independently of p53.
- Discovered that four members of the B-cell translocation gene family (Btg1, Btg2, Btg3, and Tob1) inhibit cell proliferation.
- Demonstrated that these Btg family members function in both p53-proficient and p53-deficient cells.
Conclusions:
- p19(Arf) induces a wide array of proteins that collectively contribute to cell proliferation arrest.
- The findings reveal both p53-dependent and independent pathways through which p19(Arf) exerts its tumor-suppressive functions.
- Btg family members represent key effectors in p19(Arf)-mediated cell cycle inhibition.