Deeper into the labyrinth: Functional and genetic redundancy of tumor suppressor pRb in nutrient utilization, foregut development, and cellular division

Cellular division is crucial to proper development and homeostasis in all multicellular organisms, and therefore must be tightly regulated at multiple steps, and by multiple factors capable of integrating mitogenic signals. The majority of human cancers bypass these checkpoints, unavoidably resulting in hyper-proliferation and death. The `decision' to divide is largely controlled by gate-keeper to the G1/S phase transition, retinoblastoma/pRb. The diversity of human cancers to which retinoblastoma is genetically or functionally inactivated speaks to its wide importance in cell cycle regulation. pRb was originally characterized as a transcriptional repressor, acting through the E2F family of transcription factors to regulate the transcription of genes essential to progression through S phase. A quarter century on, retinoblastoma has been found to interact with hundreds of proteins, implicating pRb in diverse aspects of development, the maintenance of chromatin structure, and genome stability.;In order to gain insight into the non-cell cycle roles of lin-35 /Rb in C. elegans development, we performed multiple genome-wide RNAi screens for suppressors of lin-35 synthetic phenotypes. Upon completion of these screens, and subsequent biochemical assays, we have clarified new roles for LIN-35/pRb in nutrient utilization, pharyngeal development, and the maintenance of somatic cell fates. The overlapping nature of these screens allowed us to identify a new class of genes specifically antagonistic to LIN-35/pRb in diverse developmental contexts. Based on this work, we hypothesize that several of the antagonistic MPLS genes represent possible cancer therapeutic targets, if inactivated in a tissue-specific manner.;We also describe redundant roles for LIN-35/pRb and essential gene PHA-1 in the development of the C. elegans foregut. Our analysis of a pharyngeal regulatory complex SUP-35/SUP-36/SUP-37 and its upstream regulators has served to partially unraveled the network of genes essential to foregut development. Furthermore, expression analysis, yeast two-hybrid screening, and a genome-wide RNAi screen have placed all three SUPs together, acting at the same temporal and spatial stage to antagonize pharynx development.;Taken together, my work has clarified novel roles for lin-35/Rb in nutrient utilization and foregut development in C. elegans, as well as contributed to a growing understanding of retinoblastoma as a crucial factor in the maintenance of somatic cell fates. Furthermore, this work contributes to a shift taking place in the understanding of pRb's role in transcriptional regulation, from a direct repressor of individual gene transcription, to a global regulator of chromatin structure.