12 research outputs found
Association of bronchopulmonary sequestration with expression of the homeobox protein Hoxb-5.
Bronchopulmonary sequestration (BPS) is caused by the abnormal development of an accessory lung diverticulum from the foregut very early in embryogenesis. The developmental abnormalities seen with BPS suggest that this anomaly is caused by abnormal expression of homeobox genes, which control axial identity and organ-specific patterning during embryogenesis. The authors previously have shown that the homeobox gene Hoxb-5 is necessary for normal airway branching during lung development. The authors now report that BPS is associated with aberrant developmental expression of Hoxb-5 protein, suggesting that this Hox gene is involved in the development of BPS
Thyroid hormone affects embryonic mouse lung branching morphogenesis and cellular differentiation
Early postnatal pulmonary failure and primary hypothyroidism in mice with combined TPST-1 and TPST-2 deficiency
Fetal heart development in the nitrofen-induced CDH rat model: the role of mechanical and nonmechanical factors
Thyroid hormone affects distal airway formation during the late pseudoglandular period of mouse lung development
Endoplasmic Reticulum Stress Decreases Intracellular Thyroid Hormone Activation via an eIF2a-Mediated Decrease in Type 2 Deiodinase Synthesis
Cells respond rapidly to endoplasmic reticulum (ER) stress by blocking protein translation, increasing protein folding capacity, and accelerating degradation of unfolded proteins via ubiquitination and ER-associated degradation pathways. The ER resident type 2 deiodinase (D2) is normally ubiquitinated and degraded in the proteasome, a pathway that is accelerated by enzyme catalysis of T(4) to T(3). To test whether D2 is normally processed through ER-associated degradation, ER stress was induced in cells that endogenously express D2 by exposure to thapsigargin or tunicamycin. In all cell models, D2 activity was rapidly lost, to as low as of 30% of control activity, without affecting D2 mRNA levels; loss of about 40% of D2 activity and protein was also seen in human embryonic kidney 293 cells transiently expressing D2. In primary human airway cells with ER stress resulting from cystic fibrosis, D2 activity was absent. The rapid ER stress-induced loss of D2 resulted in decreased intracellular D2-mediated T(3) production. ER stress-induced loss of D2 was prevented in the absence of T(4), by blocking the proteasome with MG-132 or by treatment with chemical chaperones. Notably, ER stress did not alter D2 activity half-life but rather decreased D2 synthesis as assessed by induction of D2 mRNA and by [(35)S]methionine labeling. Remarkably, ER-stress-induced loss in D2 activity is prevented in cells transiently expressing an inactive eukaryotic initiation factor 2, indicating that this pathway mediates the loss of D2 activity. In conclusion, D2 is selectively lost during ER stress due to an eukaryotic initiation factor 2-mediated decrease in D2 synthesis and sustained proteasomal degradation. This explains the lack of D2 activity in primary human airway cells with ER stress resulting from cystic fibrosis
Unique spatial and cellular expression patterns of Hoxa5, Hoxb4, and Hoxb6 proteins in normal developing murine lung are modified in pulmonary hypoplasia
Prenatal exposure to thyroid hormone is necessary for normal postnatal development of murine heart and lungs
Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling
SCOPE OF THE REVIEW: This review covers the recent advances in D2 biology, a member of the iodothyronine deiodinase family, thioredoxin fold-containing selenoenzymes that modify thyroid hormone signaling in a time- and cell-specific manner. The type II (D2) deiodinase catalyzes T4-to-T3 conversion as opposed to the type III (D3) deiodinase that terminates thyroid hormone action. MAJOR CONCLUSIONS: D2-catalyzed T3 production increases thyroid hormone signaling whereas blocking D2 activity or disruption of the Dio2 gene leads to a state of localized hypothyroidism. D2 expression is regulated by different developmental, metabolic or environmental cues such as the hedgehog pathway, the adrenergic-and the TGR5-activated cAMP pathway, by xenobiotic molecules such as flavonols and by stress in the endoplasmic reticulum, which specifically reduces de novo synthesis of D2 via an eIF2a-mediated mechanism. Thus, D2 plays a central role in important physiological processes such as determining T3 content in developing tissues and in the adult brain, and promoting adaptive thermogenesis in brown adipose tissue. Notably, D2 is critical in the T4-mediated negative feed-back at the pituitary and hypothalamic levels, whereby T4 inhibits TSH and TRH expression, respectively. Notably, ubiquitination is a major step in the control of D2 activity, whereby T4 binding to and/or T4 catalysis triggers D2 inactivation by ubiquitination that is mediated by the E3 ubiquitin ligases WSB-1 and/or TEB4. Ubiquitinated D2 can be either targeted to proteasomal degradation or reactivated by deubiquitination, a process that is mediated by the deubiquitinases USP20/33 and is important in adaptive thermogenesis. GENERAL SIGNIFICANCE: Here we review the recent advances in the understanding of D2 biology focusing on the mechanisms that regulate its expression and their biological significance in metabolically relevant tissues. This article is part of a Special Issue entitled Thyroid hormone signalling