| The cellular "decision" to divide is a carefully regulated process that utilizes myriad sensory input about the metabolic, genetic, and environmental conditions of the cell in question. A failure to heed these cues results in either uncontrolled cellular proliferation (cancer) or insufficient cell division, both of which lead, inescapably, to death. The absolute importance of this decision is underlined by the regulatory controls that are placed upon it. One critical regulator of cell division is the E2F family of transcription factors, along with their coregulator, pRb. The function of pRb is, directly or indirectly, abrogated in most human cancers, demonstrating the relevance of this pathway for disease.;In order to gain a further understanding of the roles of lin-35 /Rb in the nematode C. elegans, we performed transcriptional profiling on a lin-35/Rb putative null allele. In this process, we refined the C. elegans E2F consensus site and identified a number of novel potential E2F targets. We also hypothesize, based on our work, that lin-35/Rb is involved in regulation of neuronal and neurotransmitter genes in embryos and regulation of intestinal, ELT-2-motif-containing genes at a number of developmental stages.;This work was carried further in our characterization of a genetically redundant zinc finger transcription factor, synthetic with lin-35/Rb, which shows a highly penetrant larval arrest phenotype. Using a variety of assays, including transcriptome profiling, mosaic analysis, and starvation and expression analyses, we determined that slr-2, along with lin-35/Rb, plays a role in intestinal homeostasis. Moreover, we hypothesize that the mechanistic basis for the phenotype that we observed was the synergistic misregulation of one or more transcriptional targets shared by slr-2 and lin-35/Rb. Between these works, we began to assemble a picture of the involvement of lin-35/Rb, a classical cell cycle regulator, in novel processes, particularly in the intestine.;We also discovered that slr-2 has at least one lin-35/Rb-independent function. slr-2 is activated by a variety of stress conditions and controls transcription of a number of genes responding to these stresses. The slr-2-dependent stress response is carried out through the SARM, a consensus motif we identified in their promoters and also requires a second protein, T28F2.4. We also demonstrate that this protein, which is conserved from C. elegans to mammals, is necessary for survival in heat shock conditions in both C. elegans and D. melanogaster.;As a whole, my work helps define the developmental and non-developmental roles of lin-35/Rb and slr-2 and brings further understanding of the pathways responsible for maintenance of organism-environment homeostasis and sheds light on the cell division-arrest-apoptosis axis that is controlled by cellular stress response factors. |
