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Activation of p53 by oncogenes
1Cold Spring Harbor Laboratory, New York 11724, USA.
Abstract:
p53 is activated by a variety of cellular stresses, including DNA damage, hypoxia, and mitogenic oncogenes, but the extent to which each signal engages p53 as a tumour suppressor remains unknown. In non-immortal cells, the adenovirus E1A oncogene activates p53 to promote apoptosis, whereas oncogenic ras activates p53 to promote cellular senescence. Inactivation of p53 prevents E1A-induced apoptosis or Ras-induced senescence, allowing proliferation to continue unabated. In each instance, the ability of the oncogene to activate p53 involves the same functions as are required for their transforming potential, implying that p53 activation acts as a fail-safe mechanism to counter hyperproliferative signals. Furthermore, p19(ARF) is strictly required for oncogene signalling to p53. The fact that ARF--itself a tumour suppressor--acts as an intermediary in this response argues that the tumour suppressor activity of p53 can arise from its ability to eliminate oncogene-expressing cells.
Insights
The tumor suppressor p53 is activated by cellular stress. Oncogenes like adenovirus E1A and ras utilize p53 to induce apoptosis and senescence, respectively, acting as a fail-safe mechanism against uncontrolled cell growth.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- p53 is a critical tumor suppressor activated by various cellular stresses.
- The precise role of p53 activation in response to different oncogenic signals is not fully understood.
- Oncogenes can trigger cellular stress, leading to p53 activation.
Purpose of the Study:
- To investigate how different cellular stresses, specifically oncogenes, engage p53 as a tumor suppressor.
- To determine the mechanisms by which oncogenes like adenovirus E1A and ras activate p53.
- To elucidate the role of p19(ARF) in mediating oncogene-induced p53 activation.
Main Methods:
- Utilized non-immortal cell models.
- Introduced oncogenes such as adenovirus E1A and oncogenic ras.
- Assessed p53 activation, apoptosis, and cellular senescence.
- Investigated the requirement of p19(ARF) in the signaling pathway.
Main Results:
- Adenovirus E1A oncogene activates p53 to induce apoptosis in non-immortal cells.
- Oncogenic ras activates p53 to promote cellular senescence.
- Inactivation of p53 abrogates E1A-induced apoptosis and Ras-induced senescence, permitting uncontrolled proliferation.
- p19(ARF) is essential for oncogene signaling to p53.
Conclusions:
- p53 activation by oncogenes functions as a fail-safe mechanism to prevent hyperproliferation.
- The tumor suppressor activity of p53 can be attributed to its ability to eliminate oncogene-expressing cells.
- p19(ARF) acts as a crucial intermediary in the oncogene-p53 tumor suppressor pathway.