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A novel isoform of human LZIP negatively regulates the transactivation of the glucocorticoid receptor.

ABSTRACT: The human leucine zipper protein (LZIP) is a basic leucine zipper transcription factor that is involved in leukocyte migration, tumor suppression, and endoplasmic reticulum stress-associated protein degradation. Although evidence suggests a diversity of roles for LZIP, its function is not fully understood, and the subcellular localization of LZIP is still controversial. We identified a novel isoform of LZIP and characterized its function in ligand-induced transactivation of the glucocorticoid receptor (GR) in COS-7 and HeLa cells. A novel isoform of human LZIP designated as "sLZIP" contains a deleted putative transmembrane domain (amino acids 229-245) of LZIP and consists of 345 amino acids. LZIP and sLZIP were ubiquitously expressed in a variety of cell lines and tissues, with LZIP being much more common. sLZIP was mainly localized in the nucleus, whereas LZIP was located in the cytoplasm. Unlike LZIP, sLZIP was not involved in the chemokine-mediated signal pathway. sLZIP recruited histone deacetylases (HDACs) to the promoter region of the mouse mammary tumor virus luciferase reporter gene and enhanced the activities of HDACs, resulting in suppression of expression of the GR target genes. Our findings suggest that sLZIP functions as a negative regulator in glucocorticoid-induced transcriptional activation of GR by recruitment and activation of HDACs.

SUBMITTER: Kang H

PROVIDER: S-EPMC5419154 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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A novel isoform of human LZIP negatively regulates the transactivation of the glucocorticoid receptor.

Kang Hyereen H Kim Yoon Suk YS Ko Jesang J

Molecular endocrinology (Baltimore, Md.) 20090924 11

The human leucine zipper protein (LZIP) is a basic leucine zipper transcription factor that is involved in leukocyte migration, tumor suppression, and endoplasmic reticulum stress-associated protein degradation. Although evidence suggests a diversity of roles for LZIP, its function is not fully understood, and the subcellular localization of LZIP is still controversial. We identified a novel isoform of LZIP and characterized its function in ligand-induced transactivation of the glucocorticoid re ...[more]

PMID: 19779205

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Project description:Alternative splicing of the human glucocorticoid receptor gene generates two isoforms, hGR? and hGR?. hGR? functions as a dominant-negative regulator of hGR? activity and but also has inherent transcriptional activity, collectively altering glucocorticoid sensitivity. Single-nucleotide polymorphisms in the 3' UTR of hGR? have been associated with altered receptor protein expression, glucocorticoid sensitivity, and disease risk. Characterization of the hGR? G3134T polymorphism has been limited to a relatively small, homogenous population. The objective of this study was to determine the prevalence of hGR? G3134T in a diverse population and assess the association of hGR? G3134T in this population with physiological outcomes. In a prospective cohort study, 3730 genetically diverse participants were genotyped for hGR? G3134T and four common GR polymorphisms. A subset of these participants was evaluated for clinical and biochemical measurements. Immortalized human osteosarcoma cells (U-2 OS), stably transfected with wild-type or G3134T hGR?, were evaluated for receptor expression, stability, and genome-wide gene expression. Glucocorticoid-mediated gene expression profiles were investigated in primary macrophages isolated from participants. In a racially diverse population, the minor allele frequency was 74% (50.7% heterozygous carriers and 23.3% homozygous minor allele), with a higher prevalence in Caucasian non-Hispanic participants. After adjusting for confounding variable, carriers of hGR? G3134T were more likely to self-report allergies, have higher serum cortisol levels, and reduced cortisol suppression in response to low-dose dexamethasone. The presence of hGR? G3134T in U-2 OS cells increased hGR mRNA stability and protein expression. Microarray analysis revealed that the presence of the hGR? G3134T polymorphism uniquely altered gene expression profiles in U-2 OS cells and primary macrophages. hGR? G3134T is significantly present in the study population and associated with race, self-reported disease, and serum levels of glucocorticoids. Underlying these health differences may be changes in gene expression driven by altered receptor stability.

Dataset Information

A novel isoform of human LZIP negatively regulates the transactivation of the glucocorticoid receptor.

Publications

A novel isoform of human LZIP negatively regulates the transactivation of the glucocorticoid receptor.

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