The p53 Pathway

Mutations in the p53 pathway allow cancerous cells to avoid senescence by preventing cell-cycle arrest at the G1 to S and G2 to M transitions. TP53 is a canonical tumor suppressor gene and is subject to LOH in tumors. Germ-line mutation of p53 causes Li Fraumeni syndrome, an early-onset cancer syndrome, resulting in a broad spectrum of tumors, including cancers of the brain, breast, and blood.14 Additionally, Wilm's tumors often have germ-line mutations in TP53. Mutations in TP53 are found in more than 50% of all sporadic tumors, and, in some capacity, p53 appears to be dysregulated in every cancer. p53 functions as a tetrameric transcription factor, promoting the expression of cell-cycle arrest genes and proapo-ptotic genes in response to signals of DNA damage, aberrant growth signaling, heat shock, and other cellular stresses.7 Tumors commonly contain point mutants in the p53 DNA-binding domain, and mutations often result in the abnormal stabilization of p53. Additionally, heterozygous mutations of TP53 can function as dominant negatives for p53 function because of the tetramerization functions of p53.3,9 Finally, p53 is also a target for inactivation by human papilloma virus in cervical cancer, affirming its importance in the development of cancer.

Functional inactivation of p53 is advantageous for tumor formation because it affects two cell-cycle transition points as well as apoptotic pathways. The dual function of p53 allows the cell to stop cycling to attempt to repair damage and to undergo apoptosis if the damage is irreparable. When induced by cellular stress, p53 activates transcription of the gene for the Cip/Kip inhibitor p21 to induce both a G1 and G2-M arrest.7,9 Additional products of p53 target genes, including GADD45 and 14-3-3o, also aid in arresting the cell cycle.9 Proapoptotic p53 target genes include the genes for PUMA, Apaf-1, and Bax, a critical inhibitor of the antiapo-ptotic protein Bcl-2.9,15 A negative feedback loop is also initiated by p53-mediated transcription, increasing levels of the p53 ubiquitin ligase Hdm2, potentially allowing resumption of the cell cycle following repair of damage.

Under normal conditions, p53 is extremely unstable, but upon exposure to genotoxic stress, it is stabilized by phos-phorylation of serine residue 15 (Figure 16.3). Depending on the genotoxic stress, the kinase responsible for this phospho-rylation is either the ataxia telangiectasia-mutated (ATM) kinase or the ataxia telangiectasia and Rad3-related (ATR) kinase.3,9 Notably, inherited mutations in ATM result in cancer, although not all the ATM cancer-relevant functions involve p53. Phosphorylation of serine 15 interferes with p53 binding to the ubiquitin ligase Hdm2, blocking ubiquitina-tion of p53 and resulting in stabilization of p53. As noted earlier, stabilized p53 induces the expression of genes involved in arresting the cell cycle to allow for DNA repair but also induces proapoptotic genes if the cell cannot repair the damage. Transcriptional activation by p53 is dependent on binding to the transcriptional coactivators p300/CBP that activate p53 by acetylation of C-terminal lysines and func

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p53-mediated transcription (Hdm2. p21, ett.)

p53 degradation

Figure 16.3. Regulation of p53 activity. Phosphorylation of p53 by ataxia telangiectasia-mutated (ATM) or ataxia telangiectasia and Rad3-related (ATR) in response to DNA damage leads to the dissociation of the p53-Hdm2 complex, resulting in p53 stabilization. p14ARF inhibits the ubiquitin ligase activity of Hdm2 toward p53, resulting in p53 stabilization.

p53-mediated transcription (Hdm2. p21, ett.)

p53 degradation

Figure 16.3. Regulation of p53 activity. Phosphorylation of p53 by ataxia telangiectasia-mutated (ATM) or ataxia telangiectasia and Rad3-related (ATR) in response to DNA damage leads to the dissociation of the p53-Hdm2 complex, resulting in p53 stabilization. p14ARF inhibits the ubiquitin ligase activity of Hdm2 toward p53, resulting in p53 stabilization.

tion as a histone acetyltransferase for transcription. p53 can also be activated in response to aberrant growth signals, such as inappropriate inactivation of pRb, through a distinct pathway involving p14ARF.13 p14ARF binds to Hdm2 and prevents the polyubiquitination of p53 independent of p53 phos-phorylation.2 Activation or overexpression of E2F or c-Myc induces apoptosis through p14ARF-mediated stabilization of p53, creating a link between the pRb and p53 pathways.

Because of their functional significance to the p53 pathway, Hdm2 and p14ARF are often dysregulated in human cancer, and it is thought that the majority of tumors with wild-type p53 overexpress HDM2 or inactivate CDKN2A, the gene encoding p14ARF. In particular, p14ARF mutations are common in melanoma. Although it is not strictly required to inactivate both p53 and pRb through the same mutation event, both Hdm2 and p14ARF can become dysregulated by mechanisms that also inactivate the pRb pathway. Hdm2 is often amplified in human cancers as part of an amplicon with Cdk4, and p14ARF is often lost by deletions that affect p16INK4.2,4 The role of other proteins intimately associated with p53 in human cancer, such as p300/CBP, is less clear, although they remain a target of investigation.

How To Deal With Rosacea and Eczema

How To Deal With Rosacea and Eczema

Rosacea and Eczema are two skin conditions that are fairly commonly found throughout the world. Each of them is characterized by different features, and can be both discomfiting as well as result in undesirable appearance features. In a nutshell, theyre problems that many would want to deal with.

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