p53 is known to interact with hundreds of molecules to induce and regulate gene expression.
In normal, unstressed cells, p53 production is regulated by the binding of MDM2, which targets p53 for degradation (Thierry 1994). MDM2 is an E3 ubiquitin ligase that negatively regulates p53 by directly blocking p53 transcriptional activity and mediating p53 degradation. p53 activates the transcription of the mdm2 gene while MDM2 binds p53 and inhibits its ability to function properly (Wu et al. 1993). This forms an autoregulatory feedback loop in which MDM2 is able to control the activity of p53. In response to a stress signal, MDM2 degrades itself via polyubiquitylation, which lengthens the half-life of p53 and leads to an accumulation of p53 in the cell (Riley et al. 2008).
Activated p53 binds DNA and facilitates expression of several genes including WAF1, which encodes an important cyclin-dependent kinase inhibitor (CKI), p21. WAF1 gene expression is directly regulated by p53 and also has the ability to suppress tumor cell growth independently of p53 (El-Diery et al. 1993). This implies that WAF1 may have an important role in p53 growth suppression.
Further evidence supporting this hypothesis was shown in an experimental study involving ovarian cancer cells (Elbendary et al. 1996). The results presented in this study showed that cancerous cell lines containing mutant p53 or lacking p53 altogether, p21 levels were significantly lower than those in cancerous cells containing the fully functional wild-type p53. This implies that if mutant p53 fails to transactivate p21, aberrant cell proliferation may occur.
Although it is known that p53 binds to specific response elements in target genes, limited information exists to support an exact mechanism by which p53 activates transcription (Weintraub et al. 1991). One experiment studied the mechanism by which p53 transactivates gene transcription in muscle-specific creatine kinase (MCK), an enzyme that mediates p53 responsiveness in the cell (Jackson et al. 1998).
The MCK promoter sequence contains p53-homologous proximal and distal p53 response elements, located upstream of the transcriptional start site. The results presented in Jackson et al. showed that p53 had the greatest binding success and produced the highest level of synergistic transcriptional activation of MCK when binding as a tetramer, interacting with both proximal and distal p53 response elements. The p53-p53 interactions that link these response elements are believed to contribute to DNA looping, which provides expendable DNA for synergy. Although the way in which p53 binds and transactivates MCK has been proven, little is known about the role of p53 in the activation of other muscle-specific genes in myocyte differentiation (Ruiz-Loranzo et al. 1999).
In addition to the regulation of p53 through its transcriptional activities, several proteins are also known to influence its apoptotic function. One such protein is the retinoblastoma protein (pRb), which has been shown to both positvely and negatively regulate p53-dependent apoptosis (Kaelin, 1999).
pRb is a tumor suppressor protein that inhibits cell cycle progression and promote differentiation, preventing the proliferation of cells containing damaged or toxic DNA (Kaelin, 1999). It accomplishes this primarily through its interactions with the E2F family of transcription factors (Kaelin, 1999). Additionally, pRb is suggested to have anti-apoptotic activity (Godefroy et al. 2006). Godefroy et al. found that in both p53-dependent and p53-independent signaling pathways, stripping pRb of its function results in both unregulated cell proliferation and increased apoptosis. pRb exerts its anti-apoptotic function by antagonizing p53 apoptotic activity at multiple levels (Godefroy et al. 2006). At the transcriptional level, pRb binds and inhibits E2F, inhibiting the expression of specific proteins needed to prevent MDM2-mediated degradation of p53 (Godefroy et al. 2006). Additionally, pRb can regulate p53-induced apoptosis by acting downstream of p53 activation, promoting the expression of anti-apoptotic genes or other survival factors (Godefroy et al. 2006).
- el-Deiry, W S, T Tokino, V E Velculescu, et al. (1993). WAF1, a potential mediator of p53 tumor suppression. Cell, 75(4): 817–825.
- Elbendary, A A, F D Cirisano, A C Evans Jr, et al. (1996). Relationship between p21 expression and mutation of the p53 tumor suppressor gene in normal and malignant ovarian epithelial cells. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 2(9): 1571–1575.
- Godefroy, N., C. Lemaire, B. Mignotte, and J.-L. Vayssière. (2006).p53 and Retinoblastoma protein (pRb): A complex network of interactions. Apoptosis, 11(5): 659–661.
- Jackson, P, I Mastrangelo, M Reed, et al. (1998). Synergistic transcriptional activation of the MCK promoter by p53: tetramers link separated DNA response elements by DNA looping. Oncogene, 16(2): 283–292.
- Kaelin, W G, Jr. (1999). Functions of the retinoblastoma protein. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology, 21(11): 950–958.
- Ruiz-Lozano, P, M L Hixon, M W Wagner, et al. (1999). p53 is a transcriptional activator of the muscle-specific phosphoglycerate mutase gene and contributes in vivo to the control of its cardiac expression. Cell Growth & Differentiation: The Molecular Biology Journal of the American Association for Cancer Research, 10(5): 295–306.
- Riley, Todd, Eduardo Sontag, Patricia Chen, and Arnold Levine. (2008). Transcriptional control of human p53-regulated genes. Nature Reviews Molecular Cell Biology, 9(5): 402–412.
- Thierry Soussi. (1994). P53 Information. The TP53 Website. Retrieved 24 February 2014.
- Weintraub, H, S Hauschka, and S J Tapscott. (1991). The MCK enhancer contains a p53 responsive element.Proceedings of the National Academy of Sciences of the United States of America, 88(11): 4570–4571.
- Wu, X, J H Bayle, D Olson, and A J Levine. (1993). The p53-mdm-2 autoregulatory feedback loop. Genes & Development, 7(7A): 1126–1132.
- The p53 Wikipedia page.
- The retinoblastoma protein Wikipedia page.
- Keri: p53: Introduction
- Keri: p53: Biological function
- Keri: p53: Biosynthesis
- Keri: p53: Gene sequence
- Keri: p53: Amino acid sequence and composition
- Keri: p53: Secondary and tertiary structure
- Keri: p53: Domains and structural motifs
- Keri: p53: Interactions with macromolecules and small molecules
- Keri: p53: Molecular biodiversity and evolution
- Keri: p53: Literature overview
- Keri: p53: Useful online resources