GAR22: a novel target gene of thyroid hormone receptor causes growth inhibition in human erythroid cells.
OBJECTIVE
Thyroid hormone receptors (TRs) are ligand-dependent transcription factors with a major impact on erythroid cell development. Here we investigated TR activity on red cell gene expression and identified TR target genes. The impact of the TR target gene GAR22 (growth arrest-specific 2 [GAS2]-related gene on chromosome 22) on red cell differentiation was determined.


METHODS
Stem cell factor/erythropoietin (SCF/EPO)-dependent red cell progenitors were differentiated in vitro in the presence or absence of thyroid hormone. Hormone-induced changes in gene expression were measured by a genome-wide approach with DNA microarrays. Ectopic expression of the TR target gene GAR22 was used to determine its impact on red cell differentiation.


RESULTS
Ligand-activated TR effectively accelerated red cell progenitor differentiation in vitro concomitantly with inducing growth arrest. We demonstrate that activated TR-induced specific gene expression patterns of up- or downregulated genes, including distinct clusters associated with accelerated differentiation in response to treatment. Mining for T3-induced genes identified basic transcription element binding protein 1/Krüppel-like factor 9 (BTEB1/KLF9) and GAR22 as TR target genes. BTEB1/KLF9 is a known TR target gene while GAR22, initially identified as a putative tumor suppressor, represents a novel TR target gene. We demonstrate that ectopic GAR22 expression in red cell progenitors lengthens the cell cycle and causes growth inhibition, but leaves red cell gene expression unaffected.


CONCLUSIONS
This study identifies GAR22 as a novel and direct TR target gene. Our results suggest that hormone-induced GAR22 might represent an important trigger of growth inhibition induced by thyroid hormone in red cell progenitors.
Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany.
Ivonne
I
Gamper
Ki-Ryang
KR
Koh
David
D
Ruau
Katrin
K
Ullrich
Jana
J
Bartunkova
Daniela
D
Piroth
Christine
C
Hacker
Petr
P
Bartunek
Martin
M
Zenke
D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis; D008024:Ligands; D008840:Microfilament Proteins / Q000096:biosynthesis*; D011988:Receptors, Thyroid Hormone / Q000819:agonists / Q000378:metabolism*; D014284:Triiodothyronine / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*
C490934:GAS2L1 protein, human; C489676:KLF9 protein, human; D051741:Kruppel-Like Transcription Factors; D008024:Ligands; D008840:Microfilament Proteins; D011988:Receptors, Thyroid Hormone; D025521:Tumor Suppressor Proteins; D014284:Triiodothyronine