AARONS CUBE SIGNAL PATH ACTIVATOR

1994), indicating that it is not a potent tumor suppressor on its own. 2001), and p21 is infrequently deleted in human cancers ( Shiohara et al. However, some p21-null mice develop tumors at a late stage ( Martin-Caballero et al. p21 remains one of the p53 targets most robustly activated in response to stress and, thus, serves as a great reporter. The first identified target of p53 was the cell cycle inhibitor CDKN1A, commonly referred to as p21, with important roles in cell cycle arrest and senescence ( Brown et al. P53 transcriptionally activates multiple genes that ultimately determine whether a cell lives or dies ( Figure 1) ( Kenzelmann Broz et al. p53 is present at barely detectable levels in normal cells, but in response to stimuli such as DNA damage, ribosomal stress, metabolic stress, and other abnormalities, p53 is posttranslationally modified, leading to rapid stabilization and subsequent transactivation of hundreds of genes with multiple cellular functions ( Vousden & Prives 2009).

AARONS CUBE SIGNAL PATH ACTIVATOR

The major activity of p53 is as a transcriptional activator of a large repertoire of genes through its recognition and binding to a specific DNA sequence ( Vousden & Prives 2009). This review focuses on current concepts that have evolved from in vivo studies of the p53 pathway. The signaling pathways through which p53 functions are cell type– and context-specific, although the processes by which this occurs are still murky. Additionally, p53 has a crucial function in cell survival by promoting autophagy and metabolic restructuring in the face of starvation. However, in contrast to other tumor suppressors that are often deleted in cancers, the most common p53 mutations are missense mutations that result not only in loss of transcriptional activity but also in gain-of-function (GOF) activities that lead to aggressive tumor cell behaviors. Thus, it is the gene most often mutated in human cancers.

In this scenario, p53 is responsible for maintaining homeostasis by repairing or eliminating cells with a damaged genome ( Aylon & Oren 2016). Although p53 is under the radar most of the time, in response to DNA damage or cellular stress, such as metabolic, oxidative, or ribosomal stress, p53 functionally activates cellular processes that include cell cycle arrest, senescence, and cell death. The complexity of the p53 tumor suppressor pathway is astounding. A deeper understanding of the multiple pathways that impinge upon wild-type and mutant p53 activities and how these, in turn, regulate cell behavior will help identify vulnerabilities and therapeutic opportunities. Lastly, because mutant p53 stability is necessary for its gain of function, we summarize the mechanisms through which mutant p53 is specifically stabilized. The emerging theme is that mutant p53, which retains a potent transcriptional activation domain, also retains the ability to modify gene transcription, albeit indirectly. Numerous gain-of-function activities of mutant p53 in different model systems and contexts have been identified.

Among all p53 gene alterations identified in human cancers, p53 missense mutations predominate, suggesting an inherent biological advantage. We also summarize tissue-, stress-, and age-specific p53 activities and the potential underlying mechanisms. In this review, we first describe the current understanding of the wild-type p53 functions that determine cell survival or death, and regulation of the protein, with a particular focus on the negative regulators, the murine double minute family of proteins. The p53 tumor suppressor has been studied for decades, and still there are many questions left unanswered.

Aarons cube signal path