Cell Proliferation and Mammalian Cells
We are interested in understanding the mechanisms controlling cell proliferation and survival in mammalian cells and how deregulation of these mechanisms contributes to cancer. Our work currently focuses on two research areas: function of cyclin E-Cdk2 substrate NPAT in mammalian cells, and signaling pathways regulating the proliferation/survival of B-cell lymphomas. We anticipate that these studies will ultimately lead to the development of new approaches for cancer treatment with high specificity and efficacy.
Function of cyclin E-Cdk2 substrate NPAT
We have been interested in understanding the mechanisms of the G1-to-S phase transition in mammalian cells. One of the critical regulators of the G1/S phase transition is the cyclin-dependent kinase cyclin E-Cdk2 complex. We have identified a physiological downstream target of cyclin E-Cdk2, NPAT, and characterized its functions in cell cycle progression. We have found that NPAT plays a crucial role in coordinating transcriptional activation of all histone subtypes during the G1-to-S phase transition as well as initiation of DNA replication, suggesting that NPAT provides a critical link between cell cycle machinery and these two major S phase events and couples histone gene expression and DNA replication upon S phase entry. More recently, we have discovered that NPAT regulates cellular process in addition to cell cycle progression. These observations indicate that NPAT plays a key role in multiple cellular processes and in their coordination, which are required for maintaining genetic stability. Thus, understanding the functions and regulation of NPAT may provide new insights not only into mechanism of cellular proliferation but also into the mechanism of tumor formation. We are investigating the molecular mechanisms by which NPAT executes its multiple functions in mammalian cells.
Function of protein kinase PKK in B-cell malignancies
B-cell lymphomas are the fifth common cancer type in United States and affect nearly half a million Americans. Despite recent advances in treatment, a significant proportion of patients still die from B-cell lymphomas (approximately 20,000 people will die from the disease each year in U.S. as estimated by Lymphoma Research Foundation). Thus, new treatment strategies are needed to combat this deadly disease.
We have shown that the PKCb-associated kinase PKK is crucial for NF-kB activation in human diffuse large B cell lymphoma (DLBCL) cells. In addition, we have found that protein kinase PKK is required for NF-kB activation by BAFF (B cell activation factor belonging to the TNF family) signaling, which is emerging as a contributing factor for tumorigenesis of B-lymphocytes. Importantly, we have demonstrated that suppression of PKK expression impairs the proliferation/survival of human diffuse large B cell lymphoma (DLBCL) cells in vitro, and reduces tumor growth of xenografted DLBCL cells in NOD/SCID mice. These results suggest that PKK represents a potential therapeutic target for certain B-cell malignancies. Recently, we have identified several PKK-interacting proteins, which may also play roles in the proliferation/survival of B-lymphoma cells. We are investigating (1) the function and molecular mechanism PKK in BAFF signaling (2) the function of PKK in the proliferation/survival of other B-cell malignancies in addition to DLBCL; (3) the role of PKK in B-cell malignancies in vivo and (4) function of PKK-interacting proteins in B-cell lymphomas.