Regulation of growth and survival of activated T cells by cell-transducing inhibitors of Ras.
We describe the development of cell-penetrating inhibitors of Ras and study their ability to inhibit T cell activation. The inhibitors transduced T cells in a time and concentration-dependent manner and interacted with endogenous Ras. Anti-CD3/CD28-activated cells when treated with the inhibitors, exhibited a notable reduction in cell size, diminished proliferative capacity, and were more prone to apoptosis. Similarly, lymphocytes activated by antigen in vivo, exhibited accelerated apoptosis when treated with the inhibitors ex vivo. Our data reveal a pro-survival role for Ras in activated primary T cells and describe a new methodology for regulating its activity.
Malik
Nasser M
NM
Biochemical Pharmacology, William Harvey Research Institute, Queen Mary's School of Medicine and Dentistry, London, United Kingdom.
Gilroy
Derek W
DW
Kabouridis
Panagiotis S
PS
D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D015689:Oncogene Protein p21(ras)