A fundamental feature of all living organisms is the presence of two 24-hour oscillating cyclic systems, the circadian clock and the cell cycle. The circadian clock dictates the timing of many physiological responses and provides the cell with information that can be used to anticipate daily environmental changes. The cell cycle is a series of synchronized events involving the growth, replication, and division of cells. The proper timing of cell division is a major factor contributing to the regulation of normal growth and emerges as a fundamental process in the development of most cancers. Our laboratory investigates some of the basic mechanisms that regulate cell cycle transitions, the contribution of environmental cues to ensure timely progression throughout it, and how both cycles are interlocked at the molecular level.
Most cancer malignancies arise from the malfunction of genes that control the cellular responses to DNA-damage, as well as cell growth and division. The identification of appropriate therapeutic targets is based on a detailed understanding of the molecular changes underlying tumor growth and progression. Common cancer treatments, such as chemotherapy and radiation therapy, aim to keep cancer cells from growing by inhibiting specific steps in the cell division process. However, resistance of tumor cells to chemotherapeutic drugs and radiotherapy represents a major obstacle in these treatments. Our research will precisely define why some tumors fail to respond to radiotherapy, and how to interfere with this resistance pathway so that more effective treatment modalities can be developed.
We investigate how the circadian and cell cycle systems operating within an individual cell might be interlocked by sharing some critical elements. Recently, our lab discovered that a protein responsible for regulating the body’s sleep cycle, human protein 2, directly interacts with tumor suppressor proteins in cells to control cell division. However, if the sleep cycle is disrupted, this functionality can become impaired. Our findings on the crosstalk mechanism by which cells sense changes in environmental conditions and translate those changes in intracellular signals that promote cell division, arrest, or death open the possibility of understanding how environmental factors and life-style behaviors influence cancer incidence.
We explore how circadian factors sense metabolic changes and, consequently, act in cell-fate decisions. Here, a multi-technique approach, spanning from the atomic to the cellular level, will be used to elucidate the structural-functional properties of circadian transcription factors. Our objectives are to i) define crosstalk mechanisms among cell cycle, circadian, and metabolic components that influence cell cycle transitions ii) study the significance of metabolic signals for circadian rhythmicity and in cell death processes, and iii) determine the structural basis for sensing metabolic changes by circadian proteins. This project will help advance various areas of research by providing a mechanistic explanation for physiological changes accompanying cell division and by elucidating more fully the interplay among cellular mechanisms.
|Abigail Bock||Visiting Student|
|Helen Oker||Visiting Student|
|Alexandra Soccio-Mallon||Visiting Student|
|Esther Wisdom||Visiting Student|
|Xianlin Zou||Visiting Student|