Keith R. Johnson, PhD

Professor

Department of Oral Biology

Contact Information

Room 9.12.394, Buffett Cancer Center
987696 Nebraska Medical Center
Omaha, NE 68198-7696
402-559-3890
kjohnsonr@unmc.edu

Education

• BA, Chemistry, University of Minnesota
• BEd, Chemistry, Physics and Math Education, University of Minnesota
• PhD, Cell Biology, University of Minnesota

Teaching Responsibilities

• Course Instructor, Advanced Oral Biology (OBIO 855)

Research Interests

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:

1. 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.
2. 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.
   3. To determine 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.

Grants

Source: National Institutes of Health ID number: P20 GM103489 Title: Nebraska Center for Cellular Signaling (M.J. Wheelock, PI) Period of support: 9/19/03 – 6/30/13 The purpose of this grant is to provide career development support for junior investigators.

Source: National Institutes of Health ID number: P50 CA127297 Title: SPORE in gastrointestinal cancer: Project 2, Inhibitors of N-cadherin in the treatment of Pancreatic Cancer (M. A. Hollingsworth, PI) Period of Support: 9/16/08-9/1/13 The purpose of this grant is to study the role N-cadherin expression in pancreatic tumor cells plays in metastasis.

Source: National Institutes of Health ID number: U54 CA163120 Title: Pancreatic Tumor Micro-environment Network (S. Batra, PI) Period of Support: 9/26/11-7/31/16 The purpose of this grant is study the role N-cadherin expression in cells in the tumor microenvironment plays in tumor growth and metastasis.

Source: Department of Defense ID number: W81XWH-12-1-0390 Title: Connexin and Cadherin Cross-talk in the Pathogenesis of Prostate Cancer (Dr. Parmender Mehta, co-PI) Period of Support: 9/1/12-8/31/15 The purpose of these studies is to characterize how cadherins influence the assembly of gap junctions.

Source: National Institutes of Health ID number: R01 DE12308 (K.R. Johnson, PI)Title: Cadherins in oral squamous cell carcinomas Period of support: 04/01/98-01/31/08The long-term objective of this project is to understand how cell-cell interactions control the behavior of invasive oral squamous cell carcinomas.

Source: National Institutes of Health ID number: R01 GM51188 Title: Aspects of cadherin/catenin complexes (M.J. Wheelock, PI) Period of support: 08/01/94-7/31/10The major goals of this project were to define the roles cadherins and catenins play in cell-cell adhesion, both as structural components of the adherens junction and as signaling molecules.

Source: Nebraska Research Initiative No ID number (M.J. Wheelock, PI) Title: Cell adhesion proteins in cancers of the head and neck Period of support: 07/01/02-06/30/06The goals of this project are to identify molecular markers for head and neck cancer for use in the clinic as diagnostic and/or prognostic indicators.

Source: National Institutes of Health ID number: P20 RR18759 Title: Nebraska Center for Cellular Signaling (M.J. Wheelock, PI) Period of support: 9/19/03 – 6/30/08This grant is part of the CoBRE program to mentor junior investigators.