Intracellular signaling pathways that regulate cell fate decisions

Human cells are frequently exposed to cellular stresses, which are defined as diverse environmental conditions that are detrimental to the normal growth and survival of the cells. Typical cellular stresses include ultraviolet (UV) and ionizing radiation, genotoxins, oxidative stress, hyperosmolarity and heat shock. In coping with the barrage of these environmental stresses, multi-cellular eukaryotic organisms have developed a strategy as to how damaged cells will respond to stresses. In general, if the intensity of the damage is moderate, the cell will seek to repair the damage. If, however, the damage to a cell is too severe to be repaired, the affected cells are eliminated by apoptosis. Such a crucial decision between survival and death is mediated mainly by “MAP kinase pathways” and by the formation of “stress granules”.

MAPK signaling pathways are well conserved in all eukaryotes and consist of three tiers of protein kinases (MAPKKK-MAPKK-MAPK) (Fig. 1). In mammals, there are at least three subfamilies of MAPKs, named ERK, JNK and p38. The ERK subfamily members are activated by mitogenic stimuli and are associated with proliferative responses. In contrast, JNK and p38 are activated by environmental stresses (e.g., DNA-damaging reagents, UV irradiation, or osmotic shock) and by cytokines (e.g., IL-1 and TNFalpha), and are associated with inflammation, reparative, and/or apoptotic responses. Thus, p38 and JNK are collectively called “ stress-activated MAPKs”.

Stress granules are recently discovered cytoplasmic punctate foci (composed of mRNA and proteins) that appear when the cell is under stress. We have recently identified a novel role of stress granules in the regulation of apoptotic cell death. Formation of stress granules suppresses the activation of stress-responsive MAPK pathways, thereby inhibiting stress-induced apoptosis (Fig. 2). However, the precise function of stress-granule formation, particularly its role in the regulation of stress- and immune-responses, remains to be elucidated.

Perturbation of these critical cellular signaling systems is involved in a variety of life-threatening diseases, including cancer, autoimmune diseases, neurodegenerative disorders and type 2 diabetes. Thus they are of clinical importance. Our primary research goal is to elucidate regulatory mechanisms of cellular signaling responsible for cell fate decisions and their abnormalities in human diseases. Our laboratory also aims to develop new diagnostic and therapeutic tools for currently intractable disorders in which these pathways are involved.

The ongoing research projects in this laboratory are as follows:
Identification of;

1. The cellular sensor(s) for environmental stress.
   
2. The regulatory mechanisms of the MAPK (p38, JNK and ERK) cascades and their physiological relevance in terms of cell-fate decisions and immune responses.
   
3. The physiological and pathological functions of “Stress granules” in cellular stress responses.
   
4. The molecular mechanisms that maintain chromosomal stability and normal centrosome duplication in response to stress.
   
5. Aberrant regulation of cell signaling pathways and its pathophysiological relevance in human disorders including cancer and autoimmune diseases.
   
6. Signaling molecules that can serve as targets for therapeutic intervention and for the development of therapeutic tools.