A critical point in the cell cycle occurs in G1 phase, when cells must decide whether to enter a new round of cell division. At this time, cells assess nutrient availability to ensure that they have sufficient resources to complete cell growth and division. Vertebrate cells also assess growth factors that control cell growth and determine when and where cell division occurs in the context of a multi-cellular organism. Finally, a cell size checkpoint acts during G1 to delay entry into the cell cycle if the cell is below a critical size. When the appropriate signals have been received, cells commit to a new round of cell division by initiating transcription of G1 cyclins. The mechanisms that integrate external signals, cell growth, cell size and entry into cell cycle are poorly understood and represent a fundamental unsolved problem in cell biology. Defects in the mechanisms that control entry into the cell cycle are a primary cause of cancer. We discovered that the budding yeast Rts1 protein, a conserved regulatory subunit for protein phosphatase 2A, functions in a pathway that controls cell size and entry into the cell cycle. We further found that Rts1 is regulated by the yeast equivalent of the vertebrate PDK1/Akt signaling pathway, which plays conserved roles in the control of cell growth and entry into the cell cycle. Many components of the PDK1/Akt pathway are oncogenes. We hypothesize that Rts1 functions in pathways that integrate nutrient availability and growth rate with entry into the cell cycle. We will test this hypothesis and carry out further analysis that will provide novel insights into the conserved signaling pathways that control cell growth and entry into the cell cycle.

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The goal of our research is to elucidate the fundamental signaling pathways that control cell growth and cell division. An important focus of our work is the yeast equivalent of the vertebrate PDK1/Akt signaling pathway, which plays conserved roles in controlling cell growth and cell division. Deregulation of the PDK1/Akt pathway contributes to cancer, and significant effort is currently focused on searching for inhibitors of the pathway to identify new anticancer drugs. Thus, our research will illuminate the function and regulation of conserved signaling pathways that control cell growth and cell division, which may lead to the discovery of new ways to block the proliferation of cancer cells.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Hamlet, Michelle R
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University of California Santa Cruz
Schools of Arts and Sciences
Santa Cruz
United States
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Alcaide-Gavilán, Maria; Lucena, Rafael; Schubert, Katherine A et al. (2018) Modulation of TORC2 Signaling by a Conserved Lkb1 Signaling Axis in Budding Yeast. Genetics 210:155-170
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