In summary, our data suggest a model in which TFEB/TFE3 and p53 mutually reinforce each other’s transcriptional signaling functions and offers further evidence that disrupting TFEB and TFE3 can result in diminished p53 signaling capacity, with wide-ranging implications for renal cell carcinomas and other cancers. The gene discussed is TFE3; the disease is hereditary clear cell renal cell carcinoma.