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The transforming oncoproteins determine the mechanism by which p53 suppresses cell transformation: pRb-mediated
R Hansen1, R Reddel, A Braithwaite
1Division of Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Abstract:
To investigate the mechanisms by which p53 suppresses cell transformation, we used the simian virus 40 (SV40) large T antigen (LTag), the adenovirus E1a proteins, and an activated ras protein (EJ-ras), to examine different pathways of transformation for their susceptibility to suppression by p53: While p53 can suppress transformation by various oncoproteins, we have shown that it is unable to suppress the transformation of rat embryo fibroblasts (REFs) by LTag. Interestingly, the function of LTag which enables it to overcome the antiproliferative effects of p53 is not the binding and inactivation of p53, but the binding and inactivation of the pRb family of proteins. This observation indicates that pRb mediates a suppressive effect of p53 on cell transformation. We have also observed that in contrast to LTag, both E1a and EJ-ras cause transformation-related events which are susceptible to suppression by p53. Further studies have revealed that cells expressing E1a are susceptible to p53-mediated apoptosis, while cells expressing EJ-ras are susceptible to p53-induced growth inhibition. We therefore propose that p53 suppresses transformation either by arresting cell growth (mediated by pRb in late G1) or by inducing apoptosis, with the mechanism being determined by the transforming oncoprotein(s).
Insights
The tumor suppressor p53 inhibits cell transformation through apoptosis or growth arrest. However, simian virus 40 large T antigen overcomes p53
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- The p53 protein is a critical tumor suppressor involved in preventing cell transformation.
- Various oncoproteins, including simian virus 40 (SV40) large T antigen (LTag), adenovirus E1a, and activated ras (EJ-ras), can induce cell transformation.
- Understanding how p53 suppresses transformation and how oncoproteins evade this suppression is crucial for cancer research.
Purpose of the Study:
- To investigate the distinct mechanisms by which p53 suppresses cell transformation induced by different oncoproteins.
- To determine the role of the retinoblastoma (pRb) protein family in p53-mediated suppression of transformation.
- To elucidate whether p53 utilizes apoptosis or growth inhibition to suppress transformation.
Main Methods:
- Utilized SV40 LTag, adenovirus E1a, and EJ-ras to induce transformation in rat embryo fibroblasts (REFs).
- Assessed the susceptibility of transformation pathways to p53-mediated suppression.
- Investigated the interaction of LTag with p53 and pRb family proteins.
- Examined p53-induced apoptosis and growth inhibition in cells expressing E1a and EJ-ras, respectively.
Main Results:
- p53 suppressed transformation induced by adenovirus E1a and EJ-ras but not by SV40 LTag.
- SV40 LTag overcame p53's antiproliferative effects by binding and inactivating pRb family proteins, not p53 itself.
- Cells expressing E1a underwent p53-mediated apoptosis, while cells expressing EJ-ras experienced p53-induced growth inhibition.
Conclusions:
- pRb mediates a suppressive effect of p53 on cell transformation, and LTag's inactivation of pRb overcomes this.
- p53 suppresses transformation through either growth arrest (involving pRb in late G1) or apoptosis.
- The specific mechanism of p53-mediated suppression is dictated by the transforming oncoprotein involved.