Function in, and Mutation of, the p53 Protein: Exploring Tumor Suppression and the Development of Cancer
Authors: Kessler Eric , Bryant Rebecca , Dillavou Jack , Hiremath Aakanksha , Howard Andrew , Masoud Karim , Rast Ryan , Rosenberg Meredith , Singh Akshat , Smith Aislinn , Subramanian Kaushik , Swarts Nick 
Published: April 2020

Cancer has recently become the leading cause of death in high income countries with heart disease retaining this infamous position among middle and lower‐income countries. In the United States over 500,000 people die annually from cancer with skin, lung, prostate, breast, and colorectal cancers ranking as its most deadly forms. Cancer disproportionately impacts older adults with 70% of cases occurring in people over 50 years of age, while 5% of such cases occur in individuals younger than 15 years old. Given that the risk of developing cancer is influenced by genetic inheritance and can be caused by a variety of common environmental factors including chemical carcinogens, ionizing and ultraviolet radiation, and viruses and bacteria, what molecular machines protect us during our early life from the uncontrolled cellular division characteristic of malignant and metastasizing cancer cells? To better understand the processes underlying our bodies built in protective mechanisms the Blue Valley CAPS 2020 SMART Team (Students Modeling a Research Topic), with support of the CBM at MSOE, modeled the p53 tumor suppressor protein using JMol and 3D printing technologies. The p53 protein, a transcription activator, is coded by the TP53 gene found on the short arm of chromosome 17. It is composed of 393 amino acids and contains three distinct domains; the core DNA binding, transactivation, and tetramerization domains. Depending on the level of cellular stress and resulting DNA damage, p53 can act as a protector that leads to cell cycle arrest and tumor prevention, through either a cyclin‐dependent kinase inhibitor during G1 or the inhibition of Cdc2 during the G2/M transition, or as a killer causing apoptosis and tumor suppression through binding and regulation of bax gene transcription of Bcl‐2 which controls the release of cytochrome c from the mitochondria. Both of these actions are mediated by the DNA binding domain which displays a compact fold composed of an antiparallel b‐sheet sandwich, and a loop‐sheet‐helix motif and 2 large loops which bond directly to the major and minor grooves, respectively. The target of these interactions is with the 10 base pair consensus sequence 5’‐PuPuPuC(A/T)(T/A)GPyPyPy‐3’. The protein’s two large loops are stabilized by the coordination of a Zinc ion which steadies the loop‐sheet‐helix as well. With the overall importance of this protein as a tumor suppressor, it is understandable that 50% of all cancers involved mutations in the p53 gene, with 70% of these mutations occurring in its DNA binding domain. The majority of mutations in the DNA binding domain, 35%, occur within one of six arginine residues that are either critical for binding or for aiding in the stabilization of the binding surface. Mutations in these areas inhibit the proper function of p53 and lead to an induction of the cell cycle and blocking of apoptosis, which are characteristics of the rapidly dividing cells found in malignant tumors.