19.8: The Centrality of p53 Action in Cell Cycle Regulation

Because of its multiple roles in regulating and promoting DNA repair, and in controlling cell-cycle checkpoints, p53 has been called “the Guardian of the Genome”! Here is further evidence of this central role.

19.8.1 “Oncogenic Viruses"

Cancer-causing viruses include Human Papilloma Virus (HPV), Epstein-Barr Virus (EBV), human immunodeficiency virus (HIV), Hepatitis B and C viruses (HBV, HCV), Human Herpes Virus-8 (HHV-8), and Simian Virus 40 (SV40). The SV40 virus was discovered as a contaminant of polio vaccines which were used in the 1960s.

CHALLENGE

What are the cancers linked to these viruses?

While an association of SV40 and cancer in humans is yet unproven, there is a demonstrated link between SV40, p53, and cancer in other mammals. After an infection of cells by SV40, viral DNA enters the nucleus, where it can integrate into the host cell genome. Such SV40 infections are usually latent, meaning that they cause no harm. But when activated, they can lead to cellular transformation and the growth of malignant sarcomas in muscles, as well as tumors in other organs. If activated in an infected cell, the host-cell RNA polymerase II transcribes the SV40 genes to produce enzymes that replicate viral DNA and the viral structural proteins that encapsulate the DNA in a membrane envelope to make new viral particles. Since the relatively small SV40 genome does not encode all of the enzymes and factors needed for viral DNA replication, the infected cells also provide these factors, producing them only during the S phase. At that time, the SV40 large T antigen (already made soon after infection) enters the host-cell nucleus, where it regulates transcription of the genes essential to viral replication and viral particle formation.

All these strategies and activities may be OK for the SV40 virus, but the kicker is that the large T antigen also binds to p53, interfering with transcription of proteins whose genes are regulated by p53. Unable to exercise its normal checkpoint functions, the host cell starts dividing uncontrollably, forming cancerous tumors. Deregulation of the cell cycle by large T antigen ensures progress to the S phase and unregulated co-replication of viral and host-cell DNA.

19.8.2 p53 and Signal Transduction

Stress can activate signal transduction pathways. For example, mutations affecting the MAP-K (MAP kinase) signaling pathway can lead to tumorigenesis. This can be explained by the observation that when activated, the MAPK pathway leads to amplified production of a kinase that phosphorylates p53.

Active phospho-p53 in turn augments activation of the MAPK signal transduction pathway, and you may recall that MAPK signal transduction typically ends with a mitogenic response.

Another example of p53 interaction is with FAK (focal adhesion kinase) proteins. FAK activity is increased by integrin-mediated signal transduction. Recall that membrane integrins bind fibronectin, contributing to formation of the extracellular matrix. Elevated FAK activity participates in the regulation of cell-cell and cell-ECM adhesion at focal adhesion points. Another role for FAK is to bind directly to inactive p53 and to increase p53-Mdm2 binding. As we have just seen, persistent p53-Mdm2 is targeted for ubiquitination—and ultimate destruction! In fact, abnormally high levels of FAK are associated with many different tumor cell lines—for example, ovarian, colon, breast, thyroid, skin (melanoma), and muscle (sarcoma) cell lines. These result when p53 is unable to properly activate cell-cycle checkpoints.

While these complex interactions under active study, they certainly confirm the central role of p53 as both guardian of the genome and as guardian of cell division.