The GTPase rho controls a p53-dependent survival checkpoint during thymopoiesis.
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 beta 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 beta 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.
Costello
P S
PS
Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom.
Cleverley
S C
SC
Galandrini
R
R
Henning
S W
SW
Cantrell
D A
DA
D036002:ADP Ribose Transferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001905:Botulinum Toxins; D002470:Cell Survival; D003014:Clostridium botulinum / Q000201:enzymology / Q000235:genetics; D019254:Genes, bcl-2; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D001905:Botulinum Toxins; D020741:rho GTP-Binding Proteins