In The Response To Genotoxic Insults
The cellular tumor antigen p53 (TP53) is no doubt the most prominent tumor suppressor protein which is encoded by the TP53 gene located on the short arm of chromosome 17 (17p13.1) in humans. As it runs as a 53 kDa protein on SDS-PAGE, it was named p53 in reference to its apparent molecular mass. But calculations of amino acid residues show that p53s actual mass is 43.7 kDa. The large number of proline residues in the protein lead to its slow migration on SDS-PAGE.
p53 plays a crucial role in the cell cycle of multicellular organisms, where it is involved in cancer and functions as a tumor suppressor. In a high percentage of human tumors, p53 is always functionally impaired. ABT-263. Therefore, the strategy of activating or reactivating p53 has drawn many attentions for treating cancer, and several drugs targeting p53 have been on test in preclinical or clinical trials currently. Based on these facts and the particular role of p53 in the response to genotoxic stress and preventing genome mutation, p53 is also described as the guardian of the genome. Bcl-2 inhibitor. How does this function happen?
In the response to genotoxic insults, such as DNA damage, hypoxia, activation of oncogenes or nutrient deprivation, induce accumulation and stabilisation of the p53 which is normally expressed at a very low level in the cell. p53 constitutes a central node where the stress response pathways are integrated and the decision between cell cycle arrest, senescence, apoptosis, or other physiological processes are governed. In the cell, p53 is regulated by an autoregulatory feedback loop with an E3 ubiquitin ligase Mdm2. Nutlin-3. As shown in above figure, in response to stress signal, the Mdm2-p53 complex is dissociated by phosphorylation of both p53 and Mdm2. Primarily, enhanced p53 is accumulated in nucleus. Then, the gene encoding Mdm2 is transactivated by nuclear p53 and Mdm2 conjugates multiple ubiquitin residues of p53 and p53 is degraded. Finally, the regulatory loop is closed. Mdm2 can not only conjugate multiple ubiquitin residues, but also mono-ubiquitin residues to p53. Pomalidomide. Then, p53 is transported into the cytosol and mitochondria instead of degradation. This function contributes to the transcription-independent p53 apoptosis.
Stress signals result in three different responses by p53, binding to promoters of genes and elevating their expression levels, repressing transcription of certain genes, and exerting non-transcriptional activities. ABT-737. The response of p53 activation depends on the type of stress signal, the cell type, and the specific microenvironment. p53 activation can therefore influence cell cycle arrest in G1 and G2, senescence, DNA repair, apoptosis, angiogenesis, differentiation, autophagy and cell metabolism.
For p53, in addition to the functions as a nuclear transcription factor, it can also promote apoptosis in a transcription-independent way in the cytosol and mitochondria. We will discuss this way in my next post.
p53 plays a crucial role in the cell cycle of multicellular organisms, where it is involved in cancer and functions as a tumor suppressor. In a high percentage of human tumors, p53 is always functionally impaired. ABT-263. Therefore, the strategy of activating or reactivating p53 has drawn many attentions for treating cancer, and several drugs targeting p53 have been on test in preclinical or clinical trials currently. Based on these facts and the particular role of p53 in the response to genotoxic stress and preventing genome mutation, p53 is also described as the guardian of the genome. Bcl-2 inhibitor. How does this function happen?
In the response to genotoxic insults, such as DNA damage, hypoxia, activation of oncogenes or nutrient deprivation, induce accumulation and stabilisation of the p53 which is normally expressed at a very low level in the cell. p53 constitutes a central node where the stress response pathways are integrated and the decision between cell cycle arrest, senescence, apoptosis, or other physiological processes are governed. In the cell, p53 is regulated by an autoregulatory feedback loop with an E3 ubiquitin ligase Mdm2. Nutlin-3. As shown in above figure, in response to stress signal, the Mdm2-p53 complex is dissociated by phosphorylation of both p53 and Mdm2. Primarily, enhanced p53 is accumulated in nucleus. Then, the gene encoding Mdm2 is transactivated by nuclear p53 and Mdm2 conjugates multiple ubiquitin residues of p53 and p53 is degraded. Finally, the regulatory loop is closed. Mdm2 can not only conjugate multiple ubiquitin residues, but also mono-ubiquitin residues to p53. Pomalidomide. Then, p53 is transported into the cytosol and mitochondria instead of degradation. This function contributes to the transcription-independent p53 apoptosis.
Stress signals result in three different responses by p53, binding to promoters of genes and elevating their expression levels, repressing transcription of certain genes, and exerting non-transcriptional activities. ABT-737. The response of p53 activation depends on the type of stress signal, the cell type, and the specific microenvironment. p53 activation can therefore influence cell cycle arrest in G1 and G2, senescence, DNA repair, apoptosis, angiogenesis, differentiation, autophagy and cell metabolism.
For p53, in addition to the functions as a nuclear transcription factor, it can also promote apoptosis in a transcription-independent way in the cytosol and mitochondria. We will discuss this way in my next post.
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