This revised application aims to elucidate the role of casein kinase II in lymphomagenesis, particularly as mediated via cooperation with other oncogenes. This broadly expressed serine/threonine kinase has been found to be massively upregulated in reversible lymphoproliferative disease of cattle, and the slight overexpression of the CKIIa subunit in IgH transgenic mice leads to the slow acquisition of T cell lymphomas. Moreover, simultaneous overexpression of CKII and myc leads to the extremely rapid development of lymphomas. Based upon these data, the Applicant proposes three specific aims: 1)To measure the effects of overexpressed CKIIa' and CKIIb subunits, alone and in transgenic combination with CKIIa, on lymphomagenesis; 2)To test the hypothesis that CKII's effects are mediated by interaction with P53 by studies in CKII/P53+/- heterozygous KO mice; and 3)To study lymphomatous cell lines from CKII+ lymphomas to determine which of several lymphoid regulatory genes, including myc, myb, AP-1, p53, Rb, CREB, C/EBP, NFkB and NF-AT, might be activated by these cell lines. The Applicant believes that exploration of this system will provide insight into how post-translational modification of transcription factors by serine/threonine kinases can lead to their activation, and could contribute to the molecular pathogenesis of lymphomas and leukemias.
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