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p53 dependent growth suppression by the c-Abl nuclear tyrosine kinase
1Molecular Biology Institute, University of California, Los Angeles 90095, USA.
Abstract:
Growth suppression by the Rb and p53 tumor suppressor proteins is mediated through effects on cell cycle regulatory proteins at the G1/S transition. Because overexpression of c-Abl induces G1 arrest in fibroblasts, we reasoned that c-Abl may also affect cell cycle proteins which regulate G1. We used fibroblasts containing disruptions of the Rb or p53 genes to genetically test the role of these proteins in c-Abl growth suppression. We find that c-Abl requires p53 but not Rb to suppress growth. c-Abl binds p53 in vitro and enhances p53 dependent transcription from a promoter containing p53 DNA binding sites. An Abl mutant which no longer binds p53 does not enhance p53 transcriptional activity and fails to suppress growth. These findings provide a novel link between a growth inhibitory tyrosine kinase and the p53 tumor suppressor protein.
Insights
The c-Abl tyrosine kinase requires the p53 tumor suppressor protein, but not Rb, to inhibit cell growth. c-Abl enhances p53
Area of Science:
- Oncology
- Molecular Biology
- Cell Cycle Regulation
Background:
- Tumor suppressor proteins Rb and p53 regulate the cell cycle at the G1/S transition.
- Overexpression of c-Abl tyrosine kinase can induce G1 cell cycle arrest in fibroblasts.
Purpose of the Study:
- To investigate the role of Rb and p53 in mediating c-Abl-induced growth suppression.
- To determine if c-Abl interacts with and affects p53 function.
Main Methods:
- Utilized fibroblasts with disrupted Rb or p53 genes for genetic analysis.
- Performed in vitro binding assays to assess c-Abl and p53 interaction.
- Measured p53-dependent transcriptional activity using a reporter assay.
Main Results:
- c-Abl-mediated growth suppression is dependent on the presence of functional p53, but not Rb.
- c-Abl directly binds to p53 in vitro.
- c-Abl enhances p53's transcriptional activity on a specific promoter.
- An Abl mutant unable to bind p53 loses its growth-suppressive ability and fails to enhance p53 transcription.
Conclusions:
- The findings establish a functional link between the c-Abl tyrosine kinase and the p53 tumor suppressor.
- c-Abl's growth inhibitory function is mediated, at least in part, through its interaction with and potentiation of p53 activity.
- This interaction represents a novel mechanism in cancer cell growth regulation.