Thesis (Ph. D.)--Case Western Reserve University, 2007. / [School of Medicine] Department of Pathology. Includes bibliographical references.

Thesis (M. Phil.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

The homeodomain-interacting protein kinase (HIPK) family is comprised of four evolutionarily conserved and highly related serine/threonine kinases originally identified as co-repressors for homeodomain-containing transcription factors. While the HIPKs are most noted for regulation of apoptosis, proliferation and differentiation, I report a pleiotropic function of HIPK1 within the B cell lineage. Although lymphocyte development was normal within the thymus and bone marrow of HIPK1-deficient (HIPK1-/-) mice, the spleen exhibited a reduced number of transitional and follicular (FO) B cells, but with an increase in the marginal zone (MZ) B cell population. HIPK1-/- B cells exhibited impaired proliferation in response to B cell receptor (BCR) cross-linking in vitro; and immunization of HIPK1-/- mice with T-independent type 2 (TI-2) antigen resulted in a significantly impaired humoral response despite the expanded MZ B cell population. Immunization with T-dependent (TD) antigen resulted in a kinetically delayed response, with impaired affinity maturation. Identification of a kinase-substrate interaction between HIPK1 and the B cell adaptor 3BP2 suggests a potential context for HIPK1 function in BCR signaling. HIPK1-/- B cells were uniquely resistant to reactive oxygen species (ROS)-induced apoptosis, but equally susceptible to UV- and γ-irradiation compared to controls. In vitro class-switch recombination (CSR) assays revealed that HIPK1 is required for the negative regulation of CSR. HIPK1-/- B cell cultures harbored more viable cells, more switched cells, and elevated AID mRNA levels. The findings presented in this thesis demonstrate that HIPK1 is required for splenic B cell homeostasis and optimal BCR-responsiveness. In contrast, HIPK1 is also required for the negative regulation of CSR, possibly by mediating CSR-induced apoptosis.

The homeodomain-interacting protein kinase (HIPK) family is comprised of four evolutionarily conserved and highly related serine/threonine kinases originally identified as co-repressors for homeodomain-containing transcription factors. While the HIPKs are most noted for regulation of apoptosis, proliferation and differentiation, I report a pleiotropic function of HIPK1 within the B cell lineage. Although lymphocyte development was normal within the thymus and bone marrow of HIPK1-deficient (HIPK1-/-) mice, the spleen exhibited a reduced number of transitional and follicular (FO) B cells, but with an increase in the marginal zone (MZ) B cell population. HIPK1-/- B cells exhibited impaired proliferation in response to B cell receptor (BCR) cross-linking in vitro; and immunization of HIPK1-/- mice with T-independent type 2 (TI-2) antigen resulted in a significantly impaired humoral response despite the expanded MZ B cell population. Immunization with T-dependent (TD) antigen resulted in a kinetically delayed response, with impaired affinity maturation. Identification of a kinase-substrate interaction between HIPK1 and the B cell adaptor 3BP2 suggests a potential context for HIPK1 function in BCR signaling. HIPK1-/- B cells were uniquely resistant to reactive oxygen species (ROS)-induced apoptosis, but equally susceptible to UV- and γ-irradiation compared to controls. In vitro class-switch recombination (CSR) assays revealed that HIPK1 is required for the negative regulation of CSR. HIPK1-/- B cell cultures harbored more viable cells, more switched cells, and elevated AID mRNA levels. The findings presented in this thesis demonstrate that HIPK1 is required for splenic B cell homeostasis and optimal BCR-responsiveness. In contrast, HIPK1 is also required for the negative regulation of CSR, possibly by mediating CSR-induced apoptosis.

Thèse doctorat : Biochimie : Villeurbanne, INSA : 200. / En annexe, 1 article extrait de la revue "Journal of biological chemistry, vol. 277, n° 42, 18 oct. 2002, p. 39368-39378" Titre provenant de l'écran-titre. Bibliogr. p. 188-221.

Thesis (M. Med. Sc.)--University of Hong Kong, 2009. / Includes bibliographical references (p. 75-86).

Thesis (Ph.D)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Microbiology & Immunology. Title from title-page of electronic thesis. Bibliography: leaves 191-222.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 92-112).

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy