The objective of this proposal is to validate protein kinase C-theta (PKC- theta, a member of the PKC family, which is selectively expressed in T cells and plays an important role in mature T cell activation, as a drug target for therapeutic intervention with human T cell leukemias. This proposal derives from our recent finding with human T cell leukemias. This proposal derives from our recent finding that PKC-theta protects several types of malignant or activated T cells from Fas-or UV-induced apoptosis. Here we propose studies aimed at extending and further validating these findings.
Aim 1 is designed to establish a causative link between leukemic T cell survival or growth and PKC-theta. We will analyze the expression, intracellular localization and catalytic activity of PKC-theta in several human established T cell leukemia and a murine T cell lymphoma (EL4) in order to determine whether survival or growth of these cells is associated with constitutive PKC-theta activation. We will then determine whether experimental strategies aimed at selectively inhibiting the function of PKC-theta synergize with apoptosis-inducing regimens to facilitate apoptosis of these cells. Conversely, we will determine whether constitutively active PKC-theta confers increased resistance to apoptosis.
In Aim 2, we will extend similar analyses to several mouse in vivo models of T cell leukemias in order to determine whether selective PKC-theta-inhibiting pharmacological or genetic strategies inhibit the growth of T cell leukemias in mice, or conversely, whether an active PKC-theta transgene promotes tumor growth. These studies are likely to establish a selective role for PKC-theta in mediating survival signals, which contribute to the growth of T cell leukemias, and validate this T-cell selective enzyme as a therapeutic drug target. Combined with ongoing efforts by several pharmaceutical companies to develop selective PKC-theta inhibitors and available high throughput screening assays, the proposed studies may offer a novel therapeutic strategy for T cell leukemias.
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| Li, Yingqiu; Hu, Junru; Vita, Randi et al. (2004) SPAK kinase is a substrate and target of PKCtheta in T-cell receptor-induced AP-1 activation pathway. EMBO J 23:1112-22 |
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| Altman, Amnon; Villalba, Martin (2002) Protein kinase C-theta (PKC theta): a key enzyme in T cell life and death. J Biochem 132:841-6 |
