PROJ 11: RB PROTEIN INACTIVATION RESULTS IN A METABOLIC SHIFT TOWARDS GLUTAMINE

University Of Louisville, Louisville KY

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Retinoblastoma protein (Rb), the first described tumor suppressor, plays a vital role in regulating cell proliferation by modulating the expression of key genes involved in cell cycle progression. Although the majority of work investigating the role of Rb function in tumorigenesis has focused on cell cycle regulation, it is clear that Rb may mediate a broad spectrum of biochemical pathways, particularly those involved in cellular metabolism. Dysregulated metabolism is now considered a hallmark of tumorigenic cells, as evident by increased glucose utilization as well as a dependence on glutamine consumption. Specifically, glutamine serves to fulfill the metabolic need for energy production, nucleotide and amino acid synthesis, and the production of glutathione. Even though specific enzymes have been implicated in this phenomenon of "glutamine addiction" in tumor cells, the precise signaling mechanisms and the oncogenic factors that facilitate this metabolic shift have yet to be fully described. Using genetically depleted Rb knockout mouse embryonic fibroblasts, we demonstrate that Rb inactivation specifically leads to a dependence on glutamine for cell growth and survival. Our data further suggest that this metabolic shift may be through a c-Myc dependent pathway, as Rb depletion increases both c-Myc transcript and protein levels. At the completion of this proposal, we expect to have fully characterized the regulation of glutamine metabolism by Rb, and in doing so provide a greater understanding of the nature of the neoplastic phenotype, especially with respect to disruption of the Rb network.