Gli-similar (Glis) Krüppel-like zinc finger proteins: insights into their physiological functions and critical roles in neonatal diabetes and cystic renal disease.
GLI-similar (Glis) 1-3 proteins constitute a subfamily of the Krüppel-like zinc finger transcription factors that are closely related to the Gli family. Glis1-3 play critical roles in the regulation of a number of physiological processes and have been implicated in several pathologies. Mutations in GLIS2 have been linked to nephronophthisis, an autosomal recessive cystic kidney disease. Loss of Glis2 function leads to renal atrophy and fibrosis that involves epithelial-mesenchymal transition (EMT) of renal tubule epithelial cells. Mutations in human GLIS3 have been implicated in a syndrome characterized by neonatal diabetes and congenital hypothyroidism (NDH) and in some patients accompanied by polycystic kidney disease, glaucoma, and liver fibrosis. In addition, the GLIS3 gene has been identified as a susceptibility locus for the risk of type 1 and 2 diabetes. Glis3 plays a key role in pancreatic development, particularly in the generation of ß-cells and in the regulation of insulin gene expression. Glis2 and Glis3 proteins have been demonstrated to localize to the primary cilium, a signaling organelle that has been implicated in several pathologies, including cystic renal diseases. This association suggests that Glis2/3 are part of primary cilium-associated signaling pathways that control the activity of Glis proteins. Upon activation in the primary cilium, Glis proteins may translocate to the nucleus where they subsequently regulate gene transcription by interacting with Glis-binding sites in the promoter regulatory region of target genes. In this review, we discuss the current knowledge of the Glis signaling pathways, their physiological functions, and their involvement in several human pathologies.
Kang
Hong Soon
HS
Division of Intramural Research, Cell Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
ZeRuth
Gary
G
Lichti-Kaiser
Kristin
K
Vasanth
Shivakumar
S
Yin
Zhengyu
Z
Kim
Yong-Sik
YS
Jetten
Anton M
AM
D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology*; D003920:Diabetes Mellitus / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators; D014157:Transcription Factors / Q000502:physiology*
D004268:DNA-Binding Proteins; C508055:GLIS1 protein, human; C447919:GLIS2 protein, human; C512851:GLIS3 protein, human; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors