Keith Johnson

Biography

  Professor at Eppley Institute, Department of Oral Biology Courtesy Appointment - Department of Biochemistry & Molecular Biology  

Research Interest

 The main focus of our laboratory is the role cadherins and catenins play in tumorigenesis. Cadherins are cell-cell adhesion molecules that are the transmembrane component of the adherens junction. Catenins comprise the intracellular plaque proteins of the junction that serve to connect the cadherin to the cytoskeleton. The cadherin family of proteins has been implicated in cell sorting events during normal development. Thus, cells expressing different cadherins sort out from one another. Sorting can depend not only on expression of different family members but also on expression of different levels of a single cadherin. Tumorigenesis is a complex event that involves altered regulation of cell growth patterns and altered interactions of cells with one another and with the extracellular environment. Loss of E-cadherin function has been shown to potentiate tumor cell invasion. Loss of function may result from a mutation in the cadherin gene or from mutations in the genes that encode the catenins. Thus loss of any one of these proteins results in a non-adhesive phenotype and increased invasive potential. Interestingly, a large number of invasive tumors do not involve mutations in one of these proteins but rather downregulation of expression or activity of the adhesion complex. We are attempting to understand how the activity of the cadherin complex is regulated. One system we have chosen to study is oral squamous cell carcinoma. Oral cancers are more common than cancers of the brain, liver, kidney, thyroid, stomach, ovary or cervix. Risk factors include the use of tobacco and alcohol and exposure to environmental carcinogens. If detected early, the prognosis for survival of oral cancer is better than most cancers. An understanding of the cellular changes that occur in oral squamous cell carcinoma may suggest methods for effective early diagnosis and dramatically improve cure rates. We have shown that expression of an inappropriate member of the cadherin family (N-cadherin) by oral squamous epithelial cells results in down-regulation of the endogenous E-cadherin and generation of a cell with a more invasive phenotype. We are attempting to elucidate the mechanism by which these cellular changes occur by: Determining which domains of N-cadherin are responsible for down-regulation of the endogenous E-cadherin. These studies involve molecular construction of chimeric cadherins made up of various domains of E-cadherin linked to N-cadherin. These chimeric proteins will be tested for their ability to alter the phenotype of normal squamous epithelial cells. Determining if N-cadherin is unique in its ability to induce a more tumorigenic phenotype. Our hypothesis is that other non-epithelial cadherins may act similar to N-cadherin in this regard. We believe that the ability of a cadherin to induce these changes in epithelial cells will depend on its similarity to the cadherins expressed by mesenchymal tissues. Determining the mechanisms that confer the more invasive phenotype on N-cadherin-expressing oral squamous epithelial cells. These studies include determining alterations in signaling pathways, cellular migration and cell-substratum interactions.