Mechanism of Differentiation Functions of Cyclin Dependent Kinase 6 (Cdk6)

DESCRIPTION (provided by applicant): The experiments proposed here are aimed at investigating the mechanism of cyclin dependent kinase 6 (cdk6) in blocking differentiation and are designed to understand cdk6 function in differentiation and oncogenesis. These experimental approaches aim to enhance understanding of the mechanisms involved in the genesis of glioblastomas. Glioblastoma is the most common and lethal type of malignant glioma {Bachoo, 2002 #2}; gliomas comprise more than half of all primary brain tumors {Dai, 2001 #4}. The cdk6 protein has been found to be overexpressed in these tumors {Costello, 1997 #1; Lam, 2000 #3}. The experiments proposed here are primarily conducted in astrocytes, a type of differentiated glia from which primary brain tumors have been shown to originate {Bachoo, 2002 #2}. Proposed experiments aim to determine if the retinoblastoma tumor-suppressor protein, a known substrate of cdk6, is required to achieve previously characterized changes in morphology, expression of progenitor cell markers, and enhanced motility that have all been associated with cdk6 expression in mouse astrocytes. Also proposed are experiments designed to determine if a kinase-defective mutant of cdk6 (cdk6NFG) will cause these changes. The third set of experiments is designed to investigate the hypothesis that cdk6 phosphorylates differentiation-specific transcription factors to regulate their function, thereby regulating the process of differentiation. This hypothesis is based on the finding that cdk6 was found to bind several transcription factors in a yeast two- hybrid screen. These experiments will determine if cdk6 binds to and/or phosphorylates transcription factors to regulate their function. This project supports the mission of the NCI in that is advances our understanding of cancer, by investigating the function of a known oncogene, understanding mechanisms of cell migration, both important to the understanding of gliomas. This project will also educate and train future cancer researchers by exposing undergraduate students to high-quality cancer research. One-hundred percent of the students that have conducted research in the investigator's lab have gone on to graduate studies, professional studies, or careers in science. Indeed, data shows that liberal arts colleges produce almost twice as many eventual Ph.D.s as do other baccalaureate institutions {Connell, 2004 #7; Foundation, 1996 #6}. The experiments proposed are designed to be conducted by undergraduate students working directly with the Principle Investigator on the aims outlined above. Grossel The experiments outlined in this proposal aim to understand how a cell cycle regulatory protein and known oncogene, cyclin dependent kinase 6, functions in the process of cellular differentiation. This function of cdk6 will be studied in astroctyes, a type of glial cell that has the potential to become a glioblastoma, the most common and lethal type of glioma.

DESCRIPTION (provided by applicant): The experiments proposed here are aimed at investigating the mechanism of cyclin dependent kinase 6 (cdk6) in blocking differentiation and are designed to understand cdk6 function in differentiation and oncogenesis. These experimental approaches aim to enhance understanding of the mechanisms involved in the genesis of glioblastomas. Glioblastoma is the most common and lethal type of malignant glioma {Bachoo, 2002 #2}; gliomas comprise more than half of all primary brain tumors {Dai, 2001 #4}. The cdk6 protein has been found to be overexpressed in these tumors {Costello, 1997 #1; Lam, 2000 #3}. The experiments proposed here are primarily conducted in astrocytes, a type of differentiated glia from which primary brain tumors have been shown to originate {Bachoo, 2002 #2}. Proposed experiments aim to determine if the retinoblastoma tumor-suppressor protein, a known substrate of cdk6, is required to achieve previously characterized changes in morphology, expression of progenitor cell markers, and enhanced motility that have all been associated with cdk6 expression in mouse astrocytes. Also proposed are experiments designed to determine if a kinase-defective mutant of cdk6 (cdk6NFG) will cause these changes. The third set of experiments is designed to investigate the hypothesis that cdk6 phosphorylates differentiation-specific transcription factors to regulate their function, thereby regulating the process of differentiation. This hypothesis is based on the finding that cdk6 was found to bind several transcription factors in a yeast two- hybrid screen. These experiments will determine if cdk6 binds to and/or phosphorylates transcription factors to regulate their function. This project supports the mission of the NCI in that is advances our understanding of cancer, by investigating the function of a known oncogene, understanding mechanisms of cell migration, both important to the understanding of gliomas. This project will also educate and train future cancer researchers by exposing undergraduate students to high-quality cancer research. One-hundred percent of the students that have conducted research in the investigator's lab have gone on to graduate studies, professional studies, or careers in science. Indeed, data shows that liberal arts colleges produce almost twice as many eventual Ph.D.s as do other baccalaureate institutions {Connell, 2004 #7; Foundation, 1996 #6}. The experiments proposed are designed to be conducted by undergraduate students working directly with the Principle Investigator on the aims outlined above. Grossel The experiments outlined in this proposal aim to understand how a cell cycle regulatory protein and known oncogene, cyclin dependent kinase 6, functions in the process of cellular differentiation. This function of cdk6 will be studied in astroctyes, a type of glial cell that has the potential to become a glioblastoma, the most common and lethal type of glioma.