CPRIT-funded Research from the University of Texas MD Anderson Cancer Center presented at the 2013 AACR Annual Meeting suggests a key to sort out issues of p53 inactivation.
Associate professor at MD Anderson’s Department of Biochemistry and Molecular Biology Elsa Flores suggested that the inactivation of the p53 tumor suppressor gene is linked to the activity of p63 and p73. Research conducted in mice with induced p53 suppression confirmed that knocking out the iso-forms of p63 and p73 can help in restoration of tumor suppressor activity of p53.
“In many cancers, the tumor-suppressor p53 is inactivated by genetic mutations or is deleted outright, damage that is exploited by cancer to develop and grow. We can use the other family members to compensate for the loss of p53 as we learn more about them and how they function.”
The tumor suppressor gene p53 was first identified in 1979 as an essential component of an anti-tumor squad of the human body that controls and modulates the activity of all cells, identifying cells with genetic mutations and inducing programmed cell death in cells with irreparable DNA damage to prevent the division/growth of abnormal cells.
P63 and p73 genes were discovered in 1997 via the Human Genome Project and both the genes were identified as functionally similar to p53. However, Flores and her associates discovered that there are two isoforms of p63 and p73. This includes the transactivation versions (TAp63 and TAp73) that functions as a tumor suppressor gene just like p53 and the Delta-N versions (ΔNp63 and ΔNp73 that acts as tumor promoting genes (by deactivating or suppressing the activity of proto-oncogenes like p53).
Laboratory study and spectacular discoveries:
Flores and colleagues knocked down p63 and p73 in mice that has no p53 activity (with active thymic lymphoma). The inactivation of p63 and p73 improved the rate of tumor cell death by targeted cellular killing via tumor suppressor genes. To further ascertain the significance, Flores further injected adenoviral-CRE in the thymus to kill the p63 and p73 genes and identified that the tumor shrink within 3 weeks. The research team further identified that:
– ΔNp63 and ΔNp73 has the capacity to suppress the activity of its other isomer, TAp63 and TAp73 to decrease tumor suppression activity.
– Similar studies conducted in human models suggests that deactivation of ΔNp63 and ΔNp73 can initiate cell cycle arrest and programmed cell death (apoptosis) in tissues that are p53 deficient. Moreover, mutated p53 itself prevents the activation of tumor suppressor activity by TAp63 and TAp73.
Flores and associates are now working at developing strategies to study the effects of mutated p53 to control the gene in susceptible individuals.