Research Interests:

In maintaining integrity and homeostasis of multicellular organisms, the balance between apoptosis and cell survival is fundamentally important. When this balance is altered diseases occur such as cancer. Our laboratory is interested in defining the signal transduction pathways controlling apoptosis and survival. One of the proteins involved in the induction of apoptosis is MEK kinase 1 (MEKK1). MEKK1 is a serine threonine kinase that is cleaved by caspases into a 91kDa kinase fragment. This fragment induces apoptosis in cells. Chemotherapeutic drugs such as DNA damaging agents causes apoptosis but when the kinase inactive form of MEKK1 is expressed this apo ptosis is effectively blocked. Furthermore, MEKK1 is involved in the up-regulation of death receptors which contributes to DNA damaging drug mediated apoptosis. In the future, we will elucidate the signaling components involved in MEKK1 mediated apoptosis.

In addition to apoptosis, cell survival is important in the development of diseases. The epidermal growth factor receptor (EGFR) is expressed a high levels in several cancers such as breast cancer. The high expression of E GFR is associated with poor prognosis in breast cancer patients. We discovered that pretreatment of breast cancer cell lines with epidermal growth factor (EGF) effectively blocked FAS induced apoptosis. This protection from apoptosis is mediated by a serin e threonine kinase called AKT. We will investigate the role various tyrosine kinase receptors including EGFR family members in preventing apoptosis by a variety of apoptotic stimuli and determine the signaling components involved in this survival response

Molecular-based therapies could alter the balance between apoptosis and survival towards apoptosis in cancer cells. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) selectively kills cancer cells ranging from leukemia to breast cancer while normal cells are resistant to TRIAL-induced apoptosis. In collaboration with Dr. James Johnston, we are investigating the potential of TRAIL as a therapy for chronic lymphocytic leukemia (CLL). In addition, we are investigating the mechanism of TRAIL synergy with chemotherapeutic drugs that are used in the treatment of cancer. We previously discovered that chemotherapeutic drugs increase TRAIL death receptor (DR4/5) expression and this contributes to drug-induced apoptosis.

The goal of this research is to define the signal transduction pathways leading to apoptosis or survival. This will elucidate pharmaceutical targets that could alter the cellular balance in favour of apoptosis or survival and provided effective treatment for a variety of diseases including cancer.

Recent Publications:

1. Johnston, J. B., Kabore, A. F., Strutinsky, J., Hu, X., Paul, J. T., Kuschak B., Begleiter A, and Gibson, S. B., 2003 Role of TRAIL/APO2-L death receptors in chlorambucil- and fludarabine-induced apoptosis of primary chronic lymphocytic leukemia (CLL) cells. Oncogene, In press
2. Henson, E. S., Gibson, E. M., Bristow, N.A., Villanueva, J., Haney, N., and Gibson, S.B. 2003 Increased expression of Mcl-1 is responsible for the blockage of TRAIL-induced apoptosis mediated by EGF/ErbB1 signaling pathway. J. Cell. Biochem. 89:1177-1192. 
3. Kothari, S, Cizeau, J., McMillian-Ward, E., Isreals, S., Ens K., Kirshenbaum, L., Bailes, M., and Gibson, S.B. 2003 BNIP3 plays a role in hypoxia induced cell death and is negatively regulated by growth factors in human epithelial-derived cells. Oncogene 22: 4734-4744.PMID 12879018
4. Bild, A., Mendoza, F., Gibson, E., Villenaeuva, J., Spalding A., Sather, S., Johnson, G. L., and Gibson, S. B. 2002 Akt/PKB blocks MEKK1­induced apoptosis by inhibiting cleavage of MEKK1. Evidence for a dual role of MEKK1 in cell death. Oncogene 21:6649-6656. PMID 12242663 
5. Shetty S., Brown Gladden J., Henson E.S., Hu X., Villanueva J., Haney N., and Gibson S. B. 2002 Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) up-regulates death receptor 5 (DR5) mediated by NFkB activation in epithelial derived cell lines. Apoptosis 7:413-420.PMID 12207174 
6. Gibson, E. M., Henson, E. S., Villenaeuva, J., and Gibson, S. B. 2002 MEK kinase 1 (MEKK1) induces mitochondrial permeability transition leading to apoptosis independent of cytochrome c release. J. Biol. Chem. 277:10573-10580.PMID 11809700
7. Gibson, E. M., Henson, E.S., Villenaeuva, J., Haney, N., and Gibson S. B. 2002 Epidermal growth factor protects epithelial cells from TRAIL-induced apoptosis mediated by AKT/PKB activation. Cancer Research 62:488-496.PMID 11756439
8. Gibson, S., Oyer, R., Anderson, S., and Johnson, G., L. Increased expression of death receptors 4 and 5 synergizes the apoptosis response to combined treatment with etoposide and TRAIL. Mol. Cell Biol. 20:205-212, 2000. PMID 10594023
9. Gibson, S., Tu, S., Oyer, R., Anderson, S. and Johnson, G. L. Epidermal growth factor protects against Fas induced apoptosis: requirement of Akt activation. J. Biol. Chem. 274:17612-17618, 1999. PMID 10364198
10. Gibson, S., Widmann, C., and Johnson G. L. Differential involvement of MEKK1 in genotoxin and microtubule interfering agent induced apoptosis. J. Biol. Chem. 274:10916-10922, 1999. PMID 10196170

PubMed Listed Publications