Control of Cell Fate Determination

Research Team:  Kiyokawa, McGarry, Ardehali, Cyrns, Dimri, Gao, Eklund, Kessler, Miller, Yaseen

Normal cells have multi-layered mechanisms that govern the cell fate in response to extracellular signals and intracellular conditions. Cell fates determined by this critical process include continued cell cycle progression, differentiation with cessation of proliferation, transient arrest for damage repair (checkpoint), irreversible cell cycle arrest (senescence), and programmed cell death (apoptosis). Perturbation of cell fate determination plays a key role in cancer development. CCB members address this fundamental question from various aspects, as outlined below.

Cell cycle control (Kiyokawa, McGarry)
Perturbed cell cycle control is a hallmark of cancer. Since the basic cell cycle machinery, e.g., cyclin-dependent kinases (CDKs), are well conserved among all eukaryotic species, understanding the role of the cell cycle machinery is critical. Recent studies suggest that specific components of the cell cycle machinery are promising targets of chemotherapeutic and chemopreventive strategies. Kiyokawa has been investigating how CDKs and their regulators affect cell fate determination during development and cancer, using mouse models. Especially, he has demonstrated that the cyclin D-dependent kinase CDK4 is dispensable for development but plays an essential role in initiation of breast and skin cancers. His laboratory is currently investigating the mechanism of this action. DNA replication during S phase and mitosis during M phase must be tightly coordinated in order to maintain genomic stability. Cancer cells often exhibit mis-coordination of replication and mitosis. McGarry is studying mechanisms of this cell cycle coordination, using Xenopus laevis as a model system.

Apoptosis and cellular senescence (Ardehali, Cyrns, Dimri, Gao
Processes that govern the cell fate are critical not only for physiological development but also for cancer development. For instance, resistance to apoptosis is a major characteristic of cancer cells, while overcoming the checkpoint of cellular senescence, or immortalization, is a requisite step of carcinogenesis. Apoptosis and senescence form two major tumor suppressive mechanisms, which represent checkpoint responses to various stress and damages. Ardehali investigates the critical role of mitochondria in apoptosis. To gain novel insights into the mechanisms of apoptotic dysregulation, Cryns is taking an approach to identify and characterize caspase substrates. Gao is investigating transcriptional regulation by BRCA2 protein, the product of a key tumor suppressor gene in breast and ovarian cancers. Dimri is studying how polycomb-family transcription factors control cellular senescence.

Stem cells and differentiation (Eklund, Kessler, Miller, Yaseen)
Stem cell compartments in various tissues play a key role in tissue homeostasis. Moreover, the concept of "cancer stem cell" is now widely accepted and has significant clinical implications. Eklund and Yaseen work on transcriptional control of hematopoietic stem cells and leukemia's. Kessler investigates mechanisms of coordinated control of the cell cycle and differentiation in neuronal stem cells and progenitor cells. Miller is one of the leaders in the chemokine signaling field and he looks into the role of chemokine signaling in differentiation of glial cells and development of gliomas.

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