Basis for lineage-specific control of PTEN expression by Rpl22 (36.64)

Abstract

Abstract Mutations in a number of ribosomal proteins impair erythropoiesis (e.g., Rps19 mutations in Diamond Blackfan Anemia); however, such mutations have not been reported to disrupt T cell development. We have shown that ablation of ribosomal protein L22 (Rpl22) results in a strikingly specific defect in T cell development, selectively arresting αβ lineage cells through translational de-repression of the tumor suppressor p53 while sparing cells of the γδ-lineage. We performed comparative analysis of Rpl22-/- αβ and γδ precursors to assess the basis for lineage restriction of the blockade. Initial studies revealed a marked decrease in expression of PTEN in mixed-lineage CD4-8- (DN) progenitors from Rpl22-/- mice. This result is paradoxical, as PTEN is a positive regulator of p53 expression, yet its expression is reduced in cells where p53 is elevated. We hypothesized that the reduction in PTEN and the increase in p53 were actually occurring in distinct populations within the DN pool. Indeed, we found that PTEN levels were not reduced in purified αβ-lineage DN3 thymocytes from Rpl22-/- mice, suggesting the loss of PTEN occurs specifically in γδ lineage cells. In agreement, real-time PCR analysis revealed that PTEN mRNA levels are reduced in Rpl22-/- γδ T cells. Taken together, these data indicate that one important factor contributing to the sparing of γδ lineage development in Rpl22-/- mice is the selective reduction in γδ lineage cells of PTEN expression, which destabilizes p53.