Cell Biology Group
The Cell Biology Group recently identified a novel subfamily of Krüppel-like zinc finger proteins referred to as Gli-similar or Glis. This subfamily consists of three closely related genes named Glis1, Glis2 and Glis3. Comparison of Glis zinc finger domains (ZFDs) demonstrated that these proteins are closely related to the Gli and Zic subfamilies of Krüppel-like zinc finger proteins and share a highly conserved tandem repeat of five C2H2-type zinc finger motifs (see figure 5). Glis1 and Glis3 exhibit the highest sequence identity and may be the mammalian homologues of Drosophila gleeful/Lame duck (glf/Lmd). Although their ZFDs are highly conserved, these proteins exhibit little homology in other segments.
Glis and Gli proteins bind specific DNA elements—known as Gli-response elements (GRE)—in the promoter of target genes and can function as activators or repressors of transcription. Gli proteins act downstream of sonic hedgehog (Shh), and Shh signaling controls the proteolytic processing, nuclear localization and activation of Gli proteins. Members of the Gli, Zic and Glis families play a critical role in normal embryonic development, and are important in a number of human diseases including cancer.
Studies performed by the Cell Biology Group have demonstrated that Glis genes are expressed in a temporal and spatial manner during development suggesting that they are important in the regulation of several developmental processes. Recently, the Cell Biology Group developed mice deficient in the expression of Glis2 and Glis3. These studies indicated that the lack of Glis2 results in the development of nephropathy that subsequently leads to renal failure and premature death. (see figure 4)
An estimated 25 million Americans currently live with chronic kidney disease defined by either kidney damage or decreased kidney function. Many different conditions and factors contribute to this disease. Patients with diabetes and hypertension have a dramatically increased risk of developing nephropathy. About 25% of nephropathy patients have autoimmune disease. In addition, alloimmune response in kidney transplantation may also lead to renal failure. About 25 – 30% of cancer patients treated with chemotherapeutic agents, such as cisplatin, experience a decline in renal function that can result in renal failure. In the developing world exposure to chemicals plays an important role in the occurrence of renal dysfunction. Genetic changes in the Glis2 gene may be a factor in determining the susceptibility to chronic kidney disease, and is under investigation.
Mice deficient in Glis3 die prematurely within several days after birth. Mice develop hyperglycemia and diabetes mellitus, and have polycystic kidneys. A recent study in humans linked mutations in Glis3 to neonatal diabetes mellitus. These studies demonstrate that Glis3 plays a critical role in maintaining normal pancreatic and renal functions.
This research project has several goals.