Investigator Awards

p53 gene (human TP53) is a 53-kDa stress-responsive, genome protective, tumor suppressor protein that loses its normal function as a result of genetic alterations found in most cancers. Homozygous negative p53 tumor suppressor mice universally die of malignancy, most before 6 months of age. The Awasthi paper comprehensively demonstrates hemizygous (+/-) deficiency of Rlip ((RLIP76, RALBP1 [18p11.22]) a stress-responsive ATPase of the mercapturic acid pathway that catalyzes transmembrane efflux of glutathione (GSH)-electrophile thioether conjugates (GS-E) formed through glutathione S-transferase catalyzed conjugation of GSH with exogenous and endogenous electrophilic toxins arising from lipid peroxidation and xenobiotic exposure (ATPase activity is coupled with clathrin-dependent endocytosis (CDE)), confers protection from spontaneous malignancy in p53−/− mice, a first time observation. This discovery introduces new paradigm for p53 function, in which Rlip is a necessary effector for cancer susceptibility in p53 null mice. The study also reveals pharmacological mediated suppression of Rlip protein prevents the appearance of lymphoma or any other malignancy in p53−/− mice. // p53−/−Rlip−/+// mice are resistant to both spontaneous and chemical carcinogenesis, supporting a haplo-insufficiency mechanism. p53 loss yields genomic instability contributing to initiation and promotion of most human cancers, and to drug and radiation resistance. The Awasthi paper proposes new strategies for prevention and therapy of p53-deficient cancers either through genomic or therapeutic intervention of Rlip expression.