Department of Pathology

Cellular Pathology

Fei Chen, Ph.D.

Our goal is to understand the regulatory circuits that control the activation of transcription factor NF-kB and subsequent expression of genes involved in cell cycle regulation, cell-to-cell communication, cell migration, and cell growth. In particular, we are focusing on how upstream kinases and their cross-talks are regulated in the cellular response to environmental stress signals. The biochemical analysis of NF-kB activation is only the first step in our efforts to unravel the mechanisms that govern NF-kB activation or activity. Our long-term goal is to test whether NF-kB can be used as a therapeutic target for the control of a number of human diseases.

A principal question we must answer to understand the mechanism of NF-kB activation is how an environmental stimulus, such as oxidative stress, inflammatory cytokines, ionizing radiation, environmental or occupation dusts, that is detected at the cell surface can be transmitted to the intracellular kinase systems to initiate programs of NF-kB activation and gene expression that result in the creation of an physiological or pathological response to changes in the cellular environment. Protein kinases and phosphatases are key classes of regulatory molecules that contribute to this process. An example is represented by the IKK kinase complexes that are capable of phosphorylating endogenous NF-kB inhibitors, IkB family proteins. These kinase complexes are activated by the exposure of cells to many forms of extracellular stress by a cascade that is formed by a number of protein adaptors, ubiquitin ligases and kinases.

Our recent analysis of stress-induced NF-kB signaling revealed a mutual antagonism between MAP kinases, especially, JNK, and IKK-NF-kB. Inhibition of NF-kB by expression of a kinase-mutated IKKb (IKKb-KM) or Ikkb gene deficiency sensitizes stress responses through enhanced or prolonged JNK activation. As early as 2000, we first observed that NF-kB inhibition by expression of IKKb-KM enhanced JNK activation induced by arsenite, a classic stress inducer. Such enhanced JNK activation appeared to be responsible for the increased expression of gadd45a, a G2/M phase cell cycle regulatory gene. Later studies by other groups suggested that prolonged or enhanced JNK activation was a result of decreased expression of XIAP and/or GADD45b in the cells where NF-kB was inhibited. However, our data do not support such conclusion. Gene profiling and biochemical analysis demonstrate an increased generation of reactive oxygen species (ROS) that are responsible for the prolonged JNK activation in Ikkb gene knockout cells. Our current experiments are focused on identifying the intracellular sources of ROS and determining why inhibition of NF-kB causes oxidative stress.

Laboratory Personals:

Fei Chen, Ph.D., Principal Investigator

Murali Rao, Ph.D., Co-Principal Investigator and Medical Officer

Terry Meighan, Biologist

Scotti Matics, Summer Intern