Convergence of the thyroid hormone and gut-enriched Krüppel-like factor pathways in the context of enterocyte differentiation.
The gut-enriched Krüppel-like factor (KLF4) and the ligand-bound thyroid hormone receptor (TR) have each been shown to play a critical role in mammalian gut development and differentiation. We investigated an interrelationship between these two presumably independent pathways using the differentiation marker gene, intestinal alkaline phosphatase (IAP). Transient transfections were performed in Cos-7 cells using luciferase reporter plasmids containing a 2.5 kb segment of the proximal human IAP 5' regulatory region, as well as multiple deletions. Cells were cotransfected with TR and/or KLF4 expression vectors and treated+/-100 nmol/L thyroid hormone (T3). IAP reporter gene transactivation was increased independently by KLF4 (ninefold) and ligand-bound TR beta 1 (sevenfold). Cells cotransfected with KLF4 and TR beta 1 in the presence of T3 showed synergistic activation (70-fold). A similar pattern was seen with the other T3 receptor isoform, TR alpha 1. The synergistic effect was lost with deletions of the T3 and KLF4 response elements in the IAP promoter and was completely or partially abolished in the case of mutant KLF4 expression vectors. The thyroid hormone receptor complex and KLF4 synergistically activate the enterocyte differentiation marker gene IAP, suggesting a previously unrecognized interrelationship between these two transcription factor pathways.
Siddique
Aleem
A
Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA.
Malo
Madhu S
MS
Ocuin
Lee M
LM
Hinnebusch
Brian F
BF
Abedrapo
Mario A
MA
Henderson
J Welles
JW
Zhang
Wenying
W
Mozumder
Moushumi
M
Yang
Vincent W
VW
Hodin
Richard A
RA
D000469:Alkaline Phosphatase / Q000235:genetics*; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D019556:COS Cells; D002454:Cell Differentiation / Q000235:genetics; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics*; D020895:Enterocytes / Q000502:physiology; D058851:GPI-Linked Proteins; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014284:Triiodothyronine / Q000235:genetics*
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D058851:GPI-Linked Proteins; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; D014284:Triiodothyronine; C063088:ALPI protein, human; D000469:Alkaline Phosphatase