Restoration of thymic development in an Lck(-/-) thymoma overexpressing ZAP-70.
Thymic development is strictly controlled by Src and Syk family protein tyrosine kinases. The major players in this process are Lck and ZAP-70, which regulate critical differentiation steps of thymopoiesis. Notwithstanding the critical role of Lck and ZAP-70 in thymocyte development as compared to the related kinases Fyn and Syk, a partial functional redundancy between members of the same family of protein tyrosine kinases has emerged from studies on genetically manipulated mouse models. Furthermore, a close functional interplay between Lck and ZAP-70 in intracellular signaling has been shown to occur in thymocytes. Here we present the characterization of a thymoma from an Lck(-/-) mouse, where the block in thymocyte development is overcome and the transition between the CD4(-)CD8(-) and CD4(+)CD8(+) stages is fully restored. Determination of the expression levels of Fyn, ZAP-70 and Syk in thymocytes form the Lck(-/-) thymoma revealed high levels of ZAP-70 overexpression and recovery of a specific subset of phosphoproteins as compared to Lck(-/-) thymocytes. Hence ZAP-70 overexpression in thymocytes is associated with recovery from the developmental arrest caused by the absence of Lck, suggesting a role for ZAP-70 downstream of Lck in the maturation of CD4(+)CD8(+) thymocytes.
Ulivieri
C
C
Department of Evolutionary Biology, University of Siena, Via Mattioli 4, 53100, Siena, Italy.
Majolini
M B
MB
Baldari
C T
CT
D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000502:physiology; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn; D013601:T-Lymphocytes / Q000502:physiology*; D013945:Thymoma / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase
D015704:CD4 Antigens; D016827:CD8 Antigens; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C494960:Fyn protein, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse