Dendritic Morphology of Developing Hippocampal Neurons in Cyp11a1 Null Mice.

Introduction: Neurosteroids have a variety of neurological functions, such as neurite growth, neuroprotection, myelination, and neurogenesis. P450scc, encoded by CYP11A1 gene, is the cholesterol side chain cleavage enzyme that catalyzes the first and rate-limiting step in steroidogenesis. In this study, we examine the dendritic morphology in developing hippocampal neurons of Cyp11a1 null mice at P15, a critical period for synapse formation and maturation.

5,6-Dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) induces apoptosis in breast cancer cells through inhibiting of Mcl-1 expression.

The effective treatment of breast cancer remains a profound clinical challenge, especially due to drug resistance and metastasis which unfortunately arise in many patients. The transcription inhibitor 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB), as a selective inhibitor of cyclin-dependent kinase 9, was shown to be effective in inducing apoptosis in various hematopoietic malignancies. However, the anticancer efficacy of DRB against breast cancer is still unclear.

Expression Is Upregulated by Interleukin 4 in HT-29 Colon Cancer Cells via Multiple Signaling Pathways.

3β-Hydroxysteroid dehydrogenase/isomerase is essential for the synthesis of active steroid hormones. Interleukin 4 (IL4) induces the expression of in various human cancer cell lines. Here, we demonstrated that administration of IL4 to an HT-29 colon cancer cell line induced high expression of at the mRNA and protein levels.

PEP-sNASP Peptide Alleviates LPS-Induced Acute Lung Injury Through the TLR4/TRAF6 Axis.

Acute lung injury (ALI) is a severe inflammatory lung disease associated with macrophages. Somatic nuclear autoantigenic sperm protein (sNASP) is a negative regulator of Toll-like receptor (TLR) signaling that targets tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) in macrophages, which is required to maintain homeostasis of the innate immune response. In the present study, we generated a cell permeable PEP-sNASP peptide using the sNASP protein N-terminal domain, and examined its potential therapeutic effect in a mouse model of ALI induced by the intranasal administration of lipopolysaccharide (LPS) and elucidated the underlying molecular mechanisms in RAW 264.

Regulation of ClC-2 Chloride Channel Proteostasis by Molecular Chaperones: Correction of Leukodystrophy-Associated Defect.

The ClC-2 channel plays a critical role in maintaining ion homeostasis in the brain and the testis. Loss-of-function mutations in the ClC-2-encoding human gene are linked to the white matter disease leukodystrophy. -deficient mice display neuronal myelin vacuolation and testicular degeneration.

CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy.

Voltage-gated ClC-2 channels are essential for chloride homeostasis. Complete knockout of mouse ClC-2 leads to testicular degeneration and neuronal myelin vacuolation. Gain-of-function and loss-of-function mutations in the ClC-2-encoding human gene are linked to the genetic diseases aldosteronism and leukodystrophy, respectively.

Regulation of liver receptor homologue-1 by DDB2 E3 ligase activity is critical for hepatic glucose metabolism.

Liver receptor homologue-1 (LRH-1) plays a critical role in hepatic metabolism and disease. Here we show that LRH-1 protein stability is regulated by the cullin 4 (CUL4) E3 ubiquitin ligase complex. We found that DNA damage-binding protein 2 (DDB2) directly interacts with LRH-1 and functions as a substrate recognition component of CUL4-DDB1 to promote LRH-1 ubiquitination and proteasomal degradation.

Insulin and IGF1 receptors are essential for the development and steroidogenic function of adult Leydig cells.

The insulin family of growth factors (insulin, IGF1, and IGF2) are critical in sex determination, adrenal differentiation, and testicular function. Notably, the IGF system has been reported to mediate the proliferation of steroidogenic cells. However, the precise role and contribution of the membrane receptors mediating those effects, namely, insulin receptor (INSR) and type-I insulin-like growth factor receptor (IGF1R), have not, to our knowledge, been investigated.

Bisphenol A disrupts steroidogenesis and induces a sex hormone imbalance through c-Jun phosphorylation in Leydig cells.

Bisphenol A (BPA) is a well-known endocrine disrupting chemical (EDC) that is used to manufacture plastic consumer products. It is well known that exposure to BPA can induce defects in gonad development and negatively influences reproductive function in both males and females. In this study, we assessed the effects of BPA on hormone production in Leydig cells, which secrete hormones in the testes and support male fertility.

Proximal GATA-binding sites are essential for human HSD3B1 gene transcription in the placenta.

The enzyme 3β-hydroxysteroid dehydrogenase/isomerase (3β-HSD) is involved in the synthesis of active steroid hormones. Two human 3β-HSD isoforms are expressed in a tissue-specific pattern. HSD3B1 (type I) expression is essential to produce progesterone for pregnancy maintenance.

Ubiquitin Ligase RNF138 Promotes Episodic Ataxia Type 2-Associated Aberrant Degradation of Human Ca2.1 (P/Q-Type) Calcium Channels.

Voltage-gated Ca2.1 channels comprise a pore-forming α subunit with auxiliary αδ and β subunits. Ca2.

A calreticulin-dependent nuclear export signal is involved in the regulation of liver receptor homologue-1 protein folding.

As an orphan member of the nuclear receptor family, liver receptor homologue-1 (LRH-1) controls a tremendous range of transcriptional programmes that are essential for metabolism and hormone synthesis. Our previous studies have shown that nuclear localization of the LRH-1 protein is mediated by two nuclear localization signals (NLSs) that are karyopherin/importin-dependent. It is unclear whether LRH-1 can be actively exported from the nucleus to the cytoplasm.

The Cullin 4A/B-DDB1-Cereblon E3 Ubiquitin Ligase Complex Mediates the Degradation of CLC-1 Chloride Channels.

Voltage-gated CLC-1 chloride channels play a critical role in controlling the membrane excitability of skeletal muscles. Mutations in human CLC-1 channels have been linked to the hereditary muscle disorder myotonia congenita. We have previously demonstrated that disease-associated CLC-1 A531V mutant protein may fail to pass the endoplasmic reticulum quality control system and display enhanced protein degradation as well as defective membrane trafficking.

Local anesthetics induce apoptosis in human thyroid cancer cells through the mitogen-activated protein kinase pathway.

Local anesthetics are frequently used in fine-needle aspiration of thyroid lesions and locoregional control of persistent or recurrent thyroid cancer. Recent evidence suggests that local anesthetics have a broad spectrum of effects including inhibition of cell proliferation and induction of apoptosis in neuronal and other types of cells. In this study, we demonstrated that treatment with lidocaine and bupivacaine resulted in decreased cell viability and colony formation of both 8505C and K1 cells in a dose-dependent manner.

Local anesthetics induce apoptosis in human breast tumor cells.

Background: Previous studies have shown that local anesthetics may induce apoptosis in some cell types. In this study, we investigated the apoptotic effects of local anesthetics in human breast tumor cells.

Methods: Human breast cancer (MCF-7) and mammary epithelial (MCF-10A) cell lines were treated with lidocaine and/or bupivacaine.

Feedback control of adrenal steroidogenesis via H2O2-dependent, reversible inactivation of peroxiredoxin III in mitochondria.

Certain members of the peroxiredoxin (Prx) family undergo inactivation through hyperoxidation of the catalytic cysteine to sulfinic acid during catalysis and are reactivated by sulfiredoxin; however, the physiological significance of this reversible regulatory process is unclear. We now show that PrxIII in mouse adrenal cortex is inactivated by H(2)O(2) produced by cytochrome P450 enzymes during corticosterone production stimulated by adrenocorticotropic hormone. Inactivation of PrxIII triggers a sequence of events including accumulation of H(2)O(2), activation of p38 mitogen-activated protein kinase, suppression of steroidogenic acute regulatory protein synthesis, and inhibition of steroidogenesis.

Differential regulation of the human CYP11A1 promoter in mouse brain and adrenals.

CYP11A1 encodes the first enzyme of steroid biosynthesis, cytochrome P450scc. The expression of CYP11A1 in the nervous system allows neurosteroids to be synthesized de novo. In the classic steroidogenic tissues, adrenals and gonads, the key regulator controlling CYP11A1 expression is steroidogenic factor-1 (SF-1), but the transcriptional regulation of CYP11A1 in the brain is unclear.

Regulation of steroid production: analysis of Cyp11a1 promoter.

CYP11A1 is a key enzyme in steroid synthesis abundantly expressed in the adrenal, testis, ovary, and placenta. This article reviews recent studies on cis-regulatory elements and trans-regulators of the CYP11A1 promoter, with special focus on their tissue-specific regulation. Trans-regulators include tissue-specific factors such as SF-1, DAX-1, TReP-132, LBP, and GATA that regulate tissue-specific expression of CYP11A1.

Identification of two functional nuclear localization signals mediating nuclear import of liver receptor homologue-1.

Liver receptor homologue-1 (LRH-1) is a member of the nuclear receptor superfamily. We characterized two functional nuclear localization signals (NLSs) in LRH-1. NLS1 (residues 117-168) overlaps the second zinc finger in the DNA binding domain.

Docosahexaenoic acid induces proteasome-dependent degradation of estrogen receptor alpha and inhibits the downstream signaling target in MCF-7 breast cancer cells.

About two thirds of breast cancers in women are hormone-dependent and require estrogen for growth, its effects being mainly mediated through estrogen receptor alpha (ERalpha). Docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) have opposite effects on carcinogenesis, with DHA suppressing and AA promoting tumor growth both in vitro and in vivo. However, the mechanism is not clear.

Liver receptor homolog-1 localization in the nuclear body is regulated by sumoylation and cAMP signaling in rat granulosa cells.

Liver receptor homolog-1 (LRH-1; NR5A2) is an orphan member of the nuclear receptor superfamily, mainly expressed in endoderm-derived tissues and in the ovary. In ovarian granulosa and luteal cells, LRH-1 regulates the expression of genes associated with ovarian steroidogenesis. LRH-1 can be transported to transcriptionally inactive nuclear bodies after conjugation with small ubiquitin-related modifier (SUMO).

PIASy inhibits LRH-1-dependent CYP11A1 expression by competing for SRC-1 binding.

The orphan nuclear receptor LRH-1 (liver receptor homologue-1; NR5A2) plays a critical role in development, bile acid synthesis and cholesterol metabolism. LRH-1 is also expressed in the ovary where it is implicated in the regulation of steroidogenic genes for steroid hormone synthesis. In the present study, we investigated the molecular mechanisms of the transcriptional regulation of CYP11A1 by LRH-1 and found that LRH-1-mediated transactivation was markedly repressed by PIASy [protein inhibitor of activated STAT (signal transducer and activator of transcription) y], the shortest member of the PIAS family.

Transcriptional regulation of human CYP11A1 in gonads and adrenals.

The CYP11A1 gene encodes the cholesterol side-chain cleavage enzyme, also termed cytochrome P450scc, which catalyzes the conversion of cholesterol to pregnenolone in the first step of steroid biosynthesis in mitochondria. The adrenal- and gonad-selective, hormonally and developmentally regulated expression of CYP11A1 is principally driven by its 2.3 kb promoter.

Human CYP11A1 promoter drives Cre recombinase expression in the brain in addition to adrenals and gonads.

The first step of steroid biosynthesis is catalyzed by cytochrome P450scc, encoded by CYP11A1. To achieve steroidogenic tissue-specific inactivation of genes in vivo by the Cre-loxP approach, we used the 4.4-kb regulatory region of the human CYP11A1 gene to drive Cre recombinase expression in the tissues that produce steroids.