Beronja, SlobodanCai, Yi2019-08-142019-08-142019-08-142019Cai_washington_0250E_19857.pdfhttp://hdl.handle.net/1773/44393Thesis (Ph.D.)--University of Washington, 2019Morphologically and functionally normal human skin carries a surprisingly high burden of oncogenic lesions, suggesting that the skin has exceptional capacity to tolerate oncogene hyperactivity. To date, we have made significant progress in understanding how homeostatic adult epidermis suppresses the expansion of individual clones derived from somatic mutations. However, the mechanisms behind oncogene tolerance during epidermal development, a time of significant physiological tissue expansion, has not been explored. This is exemplified in RASopathies, where patients rarely develop epidermal defects or cancers despite germline mutations in the RAS/MAPK signaling pathway. Here, we find that oncogenic RAS-induced progenitor cell hyperproliferation is coordinated with differentiation to restrain aberrant growth and preserve epidermal development. We uncover a novel translation mechanism mediated by initiation factor eIF2B5 that co-regulates RAS proliferation and differentiation, resulting in hyperplastic but controlled growth. Using in vivo ribosome profiling, we reveal that eIF2B5 selectively regulates the translation of a substantial subset of the oncogenic RAS translatome. Furthermore, by coupling ribosome profiling with genetic screening, we provide direct functional evidence that RAS-induced differentiation is driven by eIF2B5-mediated translation of ubiquitination genes. We reveal ubiquitin ligase FBXO32 as a promoter of epidermal differentiation with no effect on proliferation, thus restraining RAS-driven pathological growth and tumorigenesis. Our study challenges the accepted view that oncogenic translation is inherently tumor promoting and unveils how it directly steers cell fate to mediate epidermal oncogene tolerance.application/pdfen-USnoneCancerDisease modelStem cell regulationMolecular biologyBiologyCellular biologyMolecular and cellular biologyThesis