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Updated: Jul 7, 2026
Purification of Ubiquitinated p53 Proteins from Mammalian Cells
Published on: March 21, 2022
In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute
E M Michalak1, A Villunger, J M Adams
1Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Abstract:
The ability of p53 to induce apoptosis in cells with damaged DNA is thought to contribute greatly to its tumour suppressor function. P53 has been proposed to induce apoptosis via numerous transcriptional targets or even by direct cytoplasmic action. Two transcriptional targets shown to mediate its apoptotic role in several cell types encode Noxa and Puma, BH3-only members of the Bcl-2 family. To test if their functions in p53-dependent apoptosis overlap, we generated mice lacking both. These mice develop normally and no tumours have yet arisen. In embryonic fibroblasts, the absence of both Noxa and Puma prevented induction of apoptosis by etoposide. Moreover, following whole body gamma-irradiation, the loss of both proteins protected thymocytes better than loss of Puma alone. Indeed, their combined deficiency protected thymocytes as strongly as loss of p53 itself. These results indicate that, at least in fibroblasts and thymocytes, p53-induced apoptosis proceeds principally via Noxa and Puma, with Puma having the predominant role in diverse cell types. The absence of tumours in the mice suggests that tumour suppression by p53 requires functions in addition to induction of apoptosis.
Insights
The tumor suppressor p53 induces apoptosis mainly through Noxa and Puma proteins. Their combined absence prevents p53-dependent apoptosis, suggesting other p53 functions are crucial for tumor suppression.
Area of Science:
- Molecular Biology
- Cellular Biology
- Genetics
Background:
- The p53 protein is a critical tumor suppressor.
- p53's tumor suppressor function is linked to its ability to induce apoptosis in cells with DNA damage.
- Noxa and Puma are key transcriptional targets of p53 that mediate apoptosis.
Purpose of the Study:
- To investigate the functional overlap between Noxa and Puma in p53-dependent apoptosis.
- To determine the primary apoptotic pathways regulated by p53.
Main Methods:
- Generation of mice lacking both Noxa and Puma genes.
- Assessment of etoposide-induced apoptosis in embryonic fibroblasts.
- Evaluation of thymocyte apoptosis following gamma-irradiation.
Main Results:
- Mice lacking both Noxa and Puma developed normally and showed no tumors.
- Absence of both Noxa and Puma prevented etoposide-induced apoptosis in fibroblasts.
- Combined deficiency of Noxa and Puma offered significant protection against gamma-irradiation-induced thymocyte apoptosis, comparable to p53 loss.
- Puma plays a predominant role in p53-induced apoptosis across various cell types.
Conclusions:
- p53-induced apoptosis in fibroblasts and thymocytes primarily relies on Noxa and Puma.
- Tumor suppression by p53 involves additional functions beyond apoptosis induction.
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