P53 protein

A protein with the innocuous name p53 is one of the most frequently cited biological molecules in the Science Citation Index. The "p" in p53 stands for protein and "53" indicates a molecular mass of 53 kDa. The p53 protein plays a fundamental role in human cell growth and mutations in this protein are frequently associated with the formation of tumors. It is estimated that of the 6.5 million people diagnosed with one or another form of cancer each year about half have p53 mutations in their tumor cells and that the vast majority of these mutations are single point mutations. 

In apoptotic cell death, several factors such as growth factors, NO, the tumor suppressor gene p53, and the protein encoded by this gene contribute to the process that leads to cell death. One of the functions of p53 protein is the activation of apoptosis if a cell is transformed to a malignant cell. Apoptosis typically leads to the formation of smaller membrane-encapsulated particles within the cell. Apoptotic cell death begins in the nucleus and proceeds to other parts of the cell. The death process may be quite advanced before it can... 

Nucleic acids in the DNA contain a high number of nucleophilic sites that can be attacked by electrophilic intermediates (metabolites) of chemical compounds. DNA adducts formed may cause alterations in the expression of a critical gene in the cell and thus lead to cell death. For example, modification of p53 tumor suppressor gene may inactivate the functions of the p53 protein and render cells sensitive to malignant transformation. Also, formation of RNA adducts may inhibit key cellular events because RNA is essential for protein synthesis. 

Liu, C., Russell, R.M., and Wang, XD. 2004. Low dose beta-carotene supplementation of ferrets attenuates smoke-induced lung phosphorylation of JNK, p38 MAPK, and p53 proteins. J Nutr 134 2705-2710. 

Another indicator of cell injury induced by genotoxic chemicals is the stabilization of p53 protein in cells. p53 is phosphorylated in response to DNA damage and strand break by the ATM and ATR pathways. Several investigators have utilized antibodies to p53 to examine increased levels of protein following chemical treatment of cells.8 9... 

Filippini, G. et al., Flow cytometric detection of p53 protein after incubation of a pre-B cell line with antitumor agents, Cytometry, 35, 267, 1999. 

Protein p63 is a member of the p53 protein family. This protein is not a specific myoepithelial marker as described in the preceding paragraph, but it is often... 

As with c-erbB, overexpression of the suppressor p53 gene product has been found in different cancers (H3). Initially, it was believed that the detection of p53 protein in tumors meant the presence of a mutant gene product. However, we now know that normal p53 protein can be overexpressed in response to certain stimuli and stabilized by interaction with both cellular and viral proteins (H3). Irrespective of the mechanism giving rise to elevated protein levels, overexpression of p53 has been shown to be a prognostic marker in both breast and colorectal cancers (D8). In some studies, the presence of high levels of p53 has been shown to be a prognostic marker in axillary node-negative breast cancer patients (H3). 

Momand, j., et ah. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell, 1992, 69(7), 1237-45. 

Kraus, A., et ah. Expression of alternatively spliced mdm2 transcripts correlates with stabilized wild-type p53 protein in human glioblastoma cells. IntJ Cancer, 1999, 80(6), 930-4. 

Freeman, D. J., et al., PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell, 2003, 3(2), 117-30. 

The p53 gene is a tumor suppressor gene, which means that its activity stops the formation of tumors via the production of p53 protein. As shown in the picture below, the p53 protein has four identical chains, which are joined together by a central tetramerization domain. The p53 protein molecule wraps around and binds DNA.This wrapping action then turns on another gene, which codes for a 21-kDa protein that regulates DNA synthesis. 

Normally, a cell grows by cell division and then dies through a process called apoptosis— programmed cell death. The p53 protein triggers apoptosis, which is a stop signal for cell division, to arrest cancer growth. 

Cells communicate to coordinate the biochemical functions within the human body. If the communication system is interrupted or messages are not conveyed fully, our bodily functions can go haywire. An example of this is discussed in Exhibit 2.2 if the p53 protein is mutated, cell growth is unchecked... 

Consequently, the concentration of the p53 protein, via p21, controls the rate of the cycle. The concentration of p53 is controlled by its rate of degradation, which is achieved by proteolysis, catalysed by the proteasome. The rate of proteolysis depends upon the phosphorylation state of p53 protein, i.e. phosphorylated-p53 is resistant to degradation and, therefore, phosphorylation results in an... 

Figure 21.12 Effect of p53 on transcription of p21 gene. The p53 protein is a transcription factor for p21, which arrests the cell cycle.

Caspase-8 activates the effector caspases either directly, or indirectly by promoting the cytochrome c (see p. 140) from mitochondria. Once in the cytoplasm, cytochrome c binds to and activates the protein Apaf-1 (not shown) and thus triggers the caspase cascade. Apoptotic signals can also come from the cell nucleus. If irreparable DNA damage is present, the p53 protein (see p. 394)—the product of a tumor suppressor gene—promotes apoptosis and thus helps eliminate the defective cell. 

Keleti, J., Quezado, M., Abaza, M., Raffeld, M., and Tsokos, M. (1996). The Mdm2 oncoprotein is overexpressed in rhabdomyosarcoma cell lines and stabilizes wild type p53 protein, Amer J Pathol 149,143-151. 

Roth ), Dobbelstein M, Freedman DA, Shenk T, Levine AJ (1998) Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein. EMBO J 17 554-564... 

Yen N, Ioannides CG, Xu K, et al. Cellular and humoral immune responses to adenovirus and p53 protein antigens in patients following intratumor injection of an adenovirus vector expressing wild-type p53 (Ad-p53). Cancer Gene Ther 2000 7 530-536. 

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