Transcription Factor CHOP

About: Transcription Factor CHOP is a research topic. Over the lifetime, 443 publications have been published within this topic receiving 46408 citations.

CHOP/GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism.

Abstract: There is increasing evidence that neuron death in neurodegenerative diseases, such as Parkinson's disease, is due to the activation of programmed cell death. However, the upstream mediators of cell death remain largely unknown. One approach to the identification of upstream mediators is to perform gene expression analysis in disease models. Such analyses, performed in tissue culture models induced by neurotoxins, have identified up-regulation of CHOP/GADD153, a transcription factor implicated in apoptosis due to endoplasmic reticulum stress or oxidative injury. To evaluate the disease-related significance of these findings, we have examined the expression of CHOP/GADD153 in neurotoxin models of parkinsonism in living animals. Nuclear expression of CHOP protein is observed in developmental and adult models of dopamine neuron death induced by intrastriatal injection of 6-hydroxydopamine (6OHDA) and in models induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). CHOP is a mediator of neuron death in the adult 60HDA model because a null mutation results in a reduction in apoptosis. In the chronic MPTP model, however, while CHOP is robustly expressed, the null mutation does not protect from the loss of neurons. We conclude that the role of CHOP depends on the nature of the toxic stimulus. For 6OHDA, an oxidative metabolite of dopamine, it is a mediator of apoptotic death.

A novel effector domain from the RNA-binding protein TLS or EWS is required for oncogenic transformation by CHOP.

Abstract: In human myxoid liposarcoma, a chromosomal rearrangement leads to fusion of the growth-arresting and DNA-damage-inducible transcription factor CHOP (GADD153) to a peptide fragment encoded by the TLS gene. We have found that wild-type TLS and a closely related sarcoma-associated protein, EWS, are both abundant nuclear proteins that associate in vivo with products of RNA polymerase II transcription. This association leads to the formation of a ternary complex with other heterogeneous RNA-binding proteins (hnRNPs), such as A1 and C1/C2. An NIH-3T3-based transformation assay was used to study the oncogenic role of the sarcoma-associated domain of these RNA-binding proteins. Transduction of the TLS-CHOP oncogene into cells by means of a retroviral expression vector leads to loss of contact inhibition, acquisition of the ability to grow as colonies in soft agar, and tumor formation in nude mice. Mutations that interfere with the function of the leucine zipper dimerization domain or the adjacent basic region of CHOP abolish transformation. The essential role of the TLS component was revealed by the inability of truncated forms to fully transform cells. Domain swap between TLS- and EWS-associated oncogenes demonstrated that the component contributed by the RNA-binding proteins are functionally interchangeable, whereas the transcription factor component specifies tumor phenotype. The sarcoma-associated component of TLS and EWS contribute a strong transcriptional activation domain to the fusion proteins; however, transforming activity cannot be fully substituted by fusion of CHOP to other strong trans-activators. The juxtaposition of a novel effector domain from sarcoma-associated RNA-binding proteins to the targeting domain of transcription factors such as CHOP leads to the creation of a potent oncogene.

Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression

Abstract: The endoplasmic reticulum (ER) stress response detects malfunctions in cellular physiology, and microbial pattern recognition receptors recognize external threats posed by infectious agents. This study has investigated whether proinflammatory cytokine expression by monocyte-derived dendritic cells is affected by the induction of ER stress. Activation of ER stress, in combination with Toll-like receptor (TLR) agonists, markedly enhanced expression of mRNA of the unique p19 subunit of IL-23, and also significantly augmented secretion of IL-23 protein. These effects were not seen for IL-12 secretion. The IL-23 gene was found to be a target of the ER stress-induced transcription factor C/EBP homologous protein (CHOP), which exhibited enhanced binding in the context of both ER stress and TLR stimulation. Knockdown of CHOP in U937 cells significantly reduced the synergistic effects of TLR and ER stress on IL-23p19 expression, but did not affect expression of other LPS-responsive genes. The integration of ER stress signals and the requirement for CHOP in the induction of IL-23 responses was also investigated in a physiological setting: infection of myeloid cells with Chlamydia trachomatis resulted in the expression of CHOP mRNA and induced the binding of CHOP to the IL-23 promoter. Furthermore, knockdown of CHOP significantly reduced the expression of IL-23 in response to this intracellular bacterium. Therefore, the effects of pathogens and other environmental factors on ER stress can profoundly affect the nature of innate and adaptive immune responses.