All ETDs from UAB

Advisory Committee Chair

Etty N Benveniste

Advisory Committee Members

Michael Brenner

Stuart J Frank

Fang-Tsyr Lin

Andrew J Paterson

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) signaling is involved in regulation of cell survival, proliferation and differentiation. JAK tyrosine kinases can be transiently activated by cytokines or growth factors in normal cells, while they become constitutively activated as a result of mutations that affect their function in tumors. Specifically, the JAK2V617F mutation is present in the majority of patients with myeloproliferative disorders (MPDs) and is implicated in the pathogenesis of these diseases. In this dissertation, we report the identification of the serine/threonine kinase CK2 as a novel interactor and important regulator of activation of the JAK-STAT signaling pathway in normal cells as well as in tumor cells. Briefly, we demonstrate that OSM-induced activation of JAKs and STATs, and expression of SOCS-3, a downstream gene, are inhibited by CK2 siRNAs or pharmacological inhibitors. IFN-γ and growth hormone (GH)-induced JAK-STAT signaling are also suppressed by inhibition of CK2 activity. Endogenous CK2α and ß are associated with JAKs, and this association is not dependent on JAK kinase activity. In addition, CK2 can phosphorylate JAK2 in vitro, which suggests that CK2 may facilitate JAK activation by interaction with and/or phos-phorylating JAKs. To extend these findings, we demonstrate that CK2 also interacts with JAK2V617F, and CK2 inhibitors suppress JAK2V617F autophosphorylation and down-stream signaling in homozygous JAK2V617F-expressing human erythroleukemia HEL92.1.7 cells (HEL). CK2 inhibitors also potently induce apoptotic cell death of HEL cells. These data provide evidence for novel crosstalk between CK2 and JAK-STAT sig-naling, with implications for cancer therapy. In addition to MPDs, constitutive activation of JAKs and STATs also mediate neoplastic transformation and promote cell prolifera-tion in many other human malignancies, such as glioblastoma (GBM). Expression of STAT-3 downstream genes such as IL-6, Mcl-1 and Pim-1 in GBM cells, which may contribute to the uncontrolled proliferation and anti-apoptotic features of GBM, can be suppressed by CK2 inhibitors. Future studies should be aimed at further clarifying the mechanisms by which CK2 regulates JAK activation by determining the interaction do-mains and phosphorylation sites of JAKs by CK2.

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