Semester

Fall

Date of Graduation

2005

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Biology

Committee Chair

Ashok Bidwai

Abstract

CK2 is a highly conserved Ser/Thr protein kinase composed of catalytic (alpha) and regulatory (beta) subunits. The enzyme targets proteins that are involved in a variety of cellular processes such as DNA replication, transcription, translation, cell cycle progression, and development. However, very little information is available on either the regulation of this enzyme or its role during development. These two aspects of CK2 have been addressed using the fruit fly, Drosophila melanogaster, as a model organism. The first study (chapter 2) addresses the isolation and characterization of SSL, an ortholog of CK2beta. Using combinatorial approaches, we find that SSL associates with CK2alpha via a domain that is indistinguishable from that in CK2beta. In addition, we find that SSL functionally mimics the biological properties of CK2beta, but exhibits an expression pattern that is non-overlapping, raising the possibility that SSL might alter the specificity of this enzyme. The second study (chapters 3 and 4) addresses the developmental role of CK2 with respect to the phosphorylation of the neural repressor E(spl)M8. We find that phosphorylation of M8 (by CK2) is essential for its ability to mediate transcriptional repression during eye development. This repression is essential for the precise positioning of neurons in the developing Drosophila retina. Using a combination of transgenics, cell-fate mapping, and mutant analysis, we implicate a role for this enzyme and identify a critical molecular target (Atonal) of phosphorylated M8. The mechanism we describe is now also implicated in the mammalian retina, where CK2 mediates the phosphorylation of Hes6, the M8 homolog. We have extended our understanding of the roles of this enzyme during neurogenesis by biochemically characterizing a novel target, Deadpan (chapter 5). Taken together, these studies have uncovered a novel evolutionarily conserved developmental role for CK2 as a regulator of neurogenesis.

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