The GTPase Rho controls a p53-dependent survival checkpoint during thymopoiesis

Patrick S. Costello, Steve C. Cleverley, Ricciarda Galandrini, Stefan W. Henning, Doreen A. Cantrell (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    53 Citations (Scopus)

    Abstract

    During the early stages of thymopoiesis, cell survival is controlled by cytokines that regulate the expression of antiapoptotic proteins such as Bcl- 2. At the pre-T cell stage, a critical checkpoint for β chain selection is monitored by the tumor suppressor p53: pre-T cells can survive and differentiate when p53 is removed genetically or when its proapoptotic function is inactivated physiologically as a consequence of signaling through the pre-T cell receptor complex. Previous work has shown that the guanine nucleotide binding protein Rho controls cell survival in T cell progenitors. Here we define the survival pathways controlled by Rho in pre-T cells and show that this GTPase is a pivotal regulator of the p53-mediated checkpoint operating at the time of β selection: loss of Rho function results in apoptosis in pre-T cells, but this cell death is prevented by loss of p53. The prevention of cell death by loss of p53 restored numbers of early T cell progenitors but did not fully restore thymic cellularity. Further analysis revealed that loss of Rho function caused survival defects in CD4/8 double- positive thymocytes that is independent of p53 but can be prevented by ectopic expression of Bcl-2. These studies highlight that the GTPase Rho is a crucial component of survival signaling pathways in at least two different thymocyte subpopulations: Rho controls the p53 survival checkpoint in pre-T cells and is also crucial for a p53 independent survival signaling pathway in CD4/8 double positives.

    Original languageEnglish
    Pages (from-to)77-85
    Number of pages9
    JournalJournal of Experimental Medicine
    Volume192
    Issue number1
    DOIs
    Publication statusPublished - 3 Jul 2000

    Keywords

    • Apoptosis
    • Development
    • Pre-T cell
    • Signaling
    • Thymus

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