Meisheng Jiang - Academia.edu (original) (raw)

Papers by Meisheng Jiang

bioRxiv (Cold Spring Harbor Laboratory), Oct 13, 2022

Cell death & disease, Jan 20, 2012

We recently identified Grainyhead-like 2 (GRHL2), a mammalian homolog of Grainyhead in Drosophila... more We recently identified Grainyhead-like 2 (GRHL2), a mammalian homolog of Grainyhead in Drosophila, to be a novel transcription factor that regulates hTERT gene expression and enhances proliferation of normal human epidermal keratinocytes (NHEK). In the current study, we show that GRHL2 impairs keratinocyte differentiation through transcriptional inhibition of the genes clustered at the epidermal differentiation complex (EDC), located at chromosome 1q21. Gene expression profiling and subsequent in vitro assays revealed consistent downregulation of EDC genes, for example, IVL, KRT1, FLG, LCEs, and SPRRs, in NHEK expressing exogenous GRHL2. In vivo binding assay by chromatin immunoprecipitation revealed GRHL2 association at the promoter regions of its target genes, many of which belong to EDC. Exogenous GRHL2 expression also inhibited recruitment of histone demethylase Jmjd3 to the EDC gene promoters and enhanced the level of histone 3 Lys 27 trimethylation enrichment at these promoter...

Hypertension, 2021

Supplemental Digital Content is available in the text. Chronic nicotine exposure significantly in... more Supplemental Digital Content is available in the text. Chronic nicotine exposure significantly increases hypertensive risk in smokers, but the underlying mechanisms are poorly understood. In the kidneys, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) catalyzes the conversion from active into inactive glucocorticoids and plays a pivotal role in the regulation of blood pressure. We hypothesized that nicotine-induced blood pressure elevation is in part mediated by change in renal 11β-HSD2 leading to higher MR (mineralocorticoid receptor) occupancy. Here, we show that nicotine exposure markedly decreased the expression and activity of renal 11β-HSD2 and increased the mean systolic arterial pressure in C57BL/6J mice. Reduction of renal 11β-HSD2 expression by nicotine was correlated with the suppression of C/EBPβ (CCAAT/enhancer-binding protein-β) and activation of Akt protein kinase phosphorylation (pThr308Akt/PKB) within the kidney. Conversely, nicotine-treated mice had elevated ren...

Investigative Ophthalmology & Visual Science, 2002

Graef Arch Clin Exp Ophthal, 1995

Molecular Genetics and Metabolism, 2006

Cytomegalic adrenal hypoplasia congenita (AHC) is an X-linked disease caused by mutations in DAX1... more Cytomegalic adrenal hypoplasia congenita (AHC) is an X-linked disease caused by mutations in DAX1-encoding gene NR0B1, previously thought to function primarily in steroidogenesis. We sought to determine the expression pattern for Dax1 along with known network partners in early embryogenesis and to determine a steroidogenic capacity for the embryo prior to the establishment of the urogenital ridge at embryonic day 9 (E9). Here, we report that murine Dax1 is a unique marker in early embryonic development, distinguishing the extraembryonic (proximal) endoderm from the remainder of the developing embryo. We showed that Wilms tumor 1, steroidogenic factor 1, and estrogen receptor b were expressed throughout the embryo, but the progesterone, estrogen a and androgen receptors, cytochrome P450 (Cyp11a1) and Nur77 were not observed in any of the embryonic layers. Lack of Cyp11A1 expression at this stage confirmed an absence of inherent steroidogenic capacity for the early embryo. The role of Nr0b1 in embryonic stem (ES) cells was investigated using siRNA knockdown, resulting in differentiation toward endoderm-like fate. Nr0b1 conditional knockout in ES cells led to differentiation, confirming our knockdown results. Our investigations suggest that Nr0b1 functions in a novel role in the maintenance of a relatively undifferentiated state. Our results further suggest that the failure of conventional murine Nr0b1 knockout attempts may be due to disregulated differentiation.

Journal of the American College of Cardiology, 2004

Background: The resting membrane potential (RMP) and cell growth in NRK cells expressing Cx43 is ... more Background: The resting membrane potential (RMP) and cell growth in NRK cells expressing Cx43 is dependent on electrical coupling between cells, which may allow molecules involved in generation of the RMP to pass from cell to cell. Since Cx45 is abundant during the early stages of mouse heart development and may participate in tissue differentiation,we studied the effect of altering the permeability of gap junction channels by co-expression of Cx43 and Cx45 on cell growth and generation of RMP. Methods: Vectors containing either-EGFP (Enhanced Green Fluorescent Protein) or EGFP and Cx45 were transfected into Cx43 expressing NRK cells. Resistant clones were grown in DMEM modified media. The RMP of the cells was measured using a single electrode patch clamp technique. Cell growth was determined daily for 4 days in both cell lines by counting cells from sister dishes after trypsinization. Results: NRK-EGFP-Cx45 demonstrated markedly decreased cell growth after 4 days as compared to NRK-EGFP. (7800±346 (Mean±SE) vs 28883±3758, N = 3, p=0.02 per paired t-test). RMP remained related to the number of cells in a cluster but show no significant difference between cell lines. Isolated cells or those with clusters of less than 3 cells had an RMP of-0.26 mV ±0.3mV. In confluent cells the RMP reached-48.04 ± 1.9 mV (NRK-EGFP) and-48.56 ±1.3 mV (NRK-EGFP-Cx45, p=0.54). 100µm 18α-glycyrrhetinic acid 3β-O-hemisuccinate(ACO) exponentially abolished the RMP with time constants of 6.12 ± 0.37 hrs and 6.67 ± 0.79 hrs. Conclusions: Co-expression of Cx45 and Cx43 results in a marked decrease in cell growth but does not appear to affect the RMP or the kinetics of uncoupling by ACO. Since the combination of connexins yields heteromeric channels with low permeability, our data strongly suggests that the mechanisms maintaining cell growth require larger permeability channels (probably for larger molecules) than the mechanism involved in establishing the RMP. NRK cells appear to be a suitable model for studying gap junction permeability and its relation to the kinetics of growth and generation of RMP. The findings could help to clarify certain aspects of cardiac development.

Journal of Biological Chemistry, 1998

Ca 2؉ release from its internal stores as a result of activation of phospholipase C is accompanie... more Ca 2؉ release from its internal stores as a result of activation of phospholipase C is accompanied by Ca 2؉ influx from the extracellular space. Ca 2؉ influx channels may be formed of proteins homologous to Drosophila Trp. At least six non-allelic Trp genes are present in the mouse genome. Full-length human, bovine, mouse, and rat cDNAs for Trp1, 3, 4, 6 have been cloned. Expression of these genes in various mammalian cells has provided evidence that Trp proteins form plasma membrane Ca 2؉-permeant channels that can be activated by an agonist that activates phospholipase C, by inositol 1,4,5trisphosphate, and/or store depletion. We have stably expressed human Trp3 (hTrp3) in human embryonic kidney (HEK)293 cells. Measurement of intracellular Ca 2؉ concentrations in Fura2-loaded cells showed that cell lines expressing hTrp3 have significantly higher basal and agonist-stimulated influxes of Ca 2؉ , Mn 2؉ , Ba 2؉ , and Sr 2؉ than control cells. The increase in Ca 2؉ entry attributable to the expression of hTrp3 obtained upon store depletion by thapsigargin was much lower than that obtained by stimulation with agonists acting via a G q-coupled receptor. Addition of agonists to thapsigargin-treated Trp3 cells resulted in a further increase in the entry of divalent cations. The increased cation entry in Trp3 cells was blocked by high concentrations of SKF 96365, verapamil, La 3؉ , Ni 2؉ , and Gd 3؉. The Trp3mediated Ca 2؉ influx activated by agonists was inhibited by a phospholipase C inhibitor, U73122. We propose that expression of hTrp3 in these cells forms a nonselective cation channel that opens after the activation of phospholipase C but not after store depletion. In addition, a subpopulation of the expressed hTrp3 may form heteromultimeric channels with endogenous proteins that are sensitive to store depletion.

Investigative Opthalmology & Visual Science, 2008

Purpose-Ocular albinism type 1 (OA1) is characterized by abnormalities in retinal pigment epithel... more Purpose-Ocular albinism type 1 (OA1) is characterized by abnormalities in retinal pigment epithelium (RPE) melanosomes and misrouting of optic axons. The OA1 gene encodes a G-proteincoupled receptor (GPCR) that coimmunoprecipitates with the Gαi-subunit of heterotrimeric Gproteins from human melanocyte extracts. This study was undertaken to test whether one of the Gαi proteins, Gαi3, signals in the same pathway as OA1 to regulate melanosome biogenesis and axonal growth through the optic chiasm. Methods-Adult Gαi3 −/− and Oa1 −/− mice were compared with their respective control mice (129Sv and B6/NCrl) to study the effects of the loss of Gαi3 or Oa1 function. Light and electron microscopy were used to analyze the morphology of the retina and the size and density of RPE melanosomes, electroretinograms to study retinal function, and retrograde labeling to investigate the size of the uncrossed optic pathway. Results-Although Gαi3 −/− and Oa1 −/− photoreceptors were comparable to those of the corresponding control retinas, the density of their RPE melanosomes was significantly lower than in control RPEs. In addition, the RPE cells of Gαi3 −/− and Oa1 −/− mice showed abnormal melanosomes that were far larger than the largest 129Sv and B6/NCrl melanosomes, respectively. Although Gαi3 −/− and Oa1 −/− mice had normal results on electroretinography, retrograde labeling showed a significant reduction from control in the size of their ipsilateral retinofugal projections. Conclusions-These results indicate that Gαi3, like Oa1, plays an important role in melanosome biogenesis. Furthermore, they suggest a common Oa1-Gαi3 signaling pathway that ultimately affects axonal growth through the optic chiasm.

Experimental Eye Research, 1995

An opsin-related gene encodes a putative RPE-retinal G-protein-coupled receptor (RGR) that is mos... more An opsin-related gene encodes a putative RPE-retinal G-protein-coupled receptor (RGR) that is most homologous to the visual pigments and invertebrate retinochrome. A splice variant of human RGR mRNA can be demonstrated by the sequence of isolated cDNA clones and by the amplification and analysis of human retinal mRNA. The shortened transcript contains a deletion of 114 nucleotides that correspond exactly to the sequence of exon 6 in the human rgr gene. The predicted RGR variant lacks the putative sixth transmembrane domain and has a calculated molecular weight of 27726. Variable amounts of a 28-kDa protein were found in the retinas of some individuals by immunoblot assay. Since a similar shortened RGR transcript was not detected in bovine retina or RPE, the RGR variant is not essential for vertebrate vision. Analysis of the structure of the rgr gene and of the sequences of cDNA clones indicates that the truncated mRNA may be produced through alternative splicing of pre-mRNA from which a cassette exon is removed and the predicted RGR variant is radically altered in primary structure.

Proceedings of the National Academy of Sciences, 2001

We reported previously that Go-deficient mice develop severe neurological defects that include hy... more We reported previously that Go-deficient mice develop severe neurological defects that include hyperalgesia, a generalized tremor, lack of coordination, and a turning syndrome somewhat reminiscent of unilateral lesions of the dopaminergic nigro-striatal pathway. By using frozen coronal sections of serially sectioned brains of normal and Go-deficient mice, we studied the ability of several G protein coupled receptors to promote binding of GTPγS to G proteins and the ability of GTP to promote a shift in the affinity of D2 dopamine receptor for its physiologic agonist dopamine. We found a generalized, but not abolished reduction in agonist-stimulated binding of GTPγS to frozen brain sections, with no significant left–right differences. Unexpectedly, the ability of GTP to regulate the binding affinity of dopamine to D2 receptors (as seen in in situ [ 35 S]sulpiride displacement curves) that was robust in control mice, was absent in Go-deficient mice. The data suggest that most of the ef...

Cell Reports, 2019

Highlights d mTOR and AMPK modulation by rapamycin, metformin, and a-KG induces anagen hair growt... more Highlights d mTOR and AMPK modulation by rapamycin, metformin, and a-KG induces anagen hair growth d Autophagy induction is necessary and sufficient for anagen entry and hair growth d Autophagy is increased during anagen phase of the natural hair follicle cycle d Aged mice fed the autophagy-inducing metabolite a-KB are protected from hair loss

SSRN Electronic Journal, 2018

Hair plays important roles, ranging from the conservation of body heat to the preservation of psy... more Hair plays important roles, ranging from the conservation of body heat to the preservation of psychological well-being. Hair loss or alopecia affects millions worldwide and can occur because of aging, hormonal dysfunction, autoimmunity, or as a side effect of cancer treatment (Gilhar et al., 2012; Petukhova et al., 2010). Methods that can be used to regrow hair are highly sought after, but lacking. Here we report that hair regeneration can be stimulated by small molecules that activate autophagy, including the longevity metabolites α-ketoglutarate and α-ketobutyrate, and the prescription drugs rapamycin and metformin which impinge on TOR and AMPK signaling.

Neurosignals, 2009

ylyl cyclase. These findings opened the door for research on the mechanisms that control hormone ... more ylyl cyclase. These findings opened the door for research on the mechanisms that control hormone action. In the early 1970s, Martin Rodbell and Lutz Birnbaumer [1] demonstrated that guanosine nucleotide triphosphate (GTP) is required for stimulation of adenylyl cyclase activity in adipocyte membrane preparations. Further investigation revealed that GTP affects hormone receptorbinding properties. The discovery of a GTP requirement for transducing extracellular signals into cells provided the basis for the existence of GTP-binding G proteins (formally referred to as N proteins for nucleotide-binding protein). In the late 1970s, Alfred Gilman and associates [2, 3] isolated and identified the first GTP-binding protein, Gs (stimulatory regulator of adenylyl cyclase G protein) and provided direct evidence that the GTP-binding protein acts as a signaling molecule in hormone signaling. Meanwhile, another GTP-binding protein, transducin (Gt), was identified as a signal transducer in bovine retina [4]. Transducins, abundant in the outer retinal segments, couple rhodopsin to cyclic GMP-dependent phosphodiesterase and transmit incoming photons into chemical signals. The use of two bacterial toxins has greatly facilitated the identification and characterization of G proteins. Cholera toxin, from Vibrio cholerae bacteria, mediates ADP ribosylation of the Gs protein and was used in the early characterization and purification of Gs [5-7]. Bordetella pertussis toxin (PTX), discovered as the islet-activating protein, mediates the ADP ribosylation of Gi proteins (which inhibit adenylyl cyclase activity) [8, 9]. Treatment of cells or membranes with PTX results in the loss

Clinical Science, 2019

Excessive glucocorticoid (GC) production in adipose tissue promotes the development of visceral o... more Excessive glucocorticoid (GC) production in adipose tissue promotes the development of visceral obesity and metabolic syndrome (MS). 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is critical for controlling intracellular GC production, and this process is tightly regulated by hexose-6-phosphate dehydrogenase (H6PDH). To better understand the integrated molecular physiological effects of adipose H6PDH, we created a tissue-specific knockout of the H6PDH gene mouse model in adipocytes (adipocyte-specific conditional knockout of H6PDH (H6PDHAcKO) mice). H6PDHAcKO mice exhibited almost complete absence of H6PDH expression and decreased intra-adipose corticosterone production with a reduction in 11β-HSD1 activity in adipose tissue. These mice also had decreased abdominal fat mass, which was paralleled by decreased adipose lipogenic acetyl-CoA carboxylase (ACC) and ATP-citrate lyase (ACL) gene expression and reduction in their transcription factor C/EBPα mRNA levels. Moreover, H6PDHAc...

AJP: Endocrinology and Metabolism, 2013

The prereceptor activation of glucocorticoid production in adipose tissue by NADPH-dependent 11β-... more The prereceptor activation of glucocorticoid production in adipose tissue by NADPH-dependent 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has emerged as a potential mechanism in the pathogenesis of visceral obesity and metabolic syndrome. Hexose-6-phosphate dehydrogenase (H6PDH) is an endoplasmic reticulum lumen-resident enzyme that generates cofactor NADPH and thus mediates 11β-HSD1 activity. To determine the role of adipose H6PDH in the prereceptor modulation of 11β-HSD1 and metabolic phenotypes, we generated a transgenic (Tg) mouse model overexpressing H6PDH under the control of the enhancer-promoter region of the adipocyte fatty acid-binding protein (aP2) gene (aP2/H6PDH Tg mice). Transgenic aP2/H6PDH mice exhibited relatively high expression of H6PDH and elevated corticosterone production with induction of 11β-HSD1 activity in adipose tissue. This increase in corticosterone production in aP2-H6PDH Tg mice resulted in mild abdominal fat accumulation with induction of C/EBP...

Sandra Winter,1* Irene Brunk,1* Diego J. Walther,2 Markus Höltje,1 Meisheng Jiang,3 Jens-Uwe Pete... more Sandra Winter,1* Irene Brunk,1* Diego J. Walther,2 Markus Höltje,1 Meisheng Jiang,3 Jens-Uwe Peter,2 Shigeo Takamori,4 Reinhard Jahn,4 Lutz Birnbaumer,3 and Gudrun Ahnert-Hilger1 1AG Funktionelle Zellbiologie, Centrum für Anatomie, Charité Universitätsmedizin Berlin, D-10115 Berlin, Germany, 2Max-Planck-Institut für Molekulare Genetik, D-14195 Berlin, Germany, 3National Institute of Environmental Health Sciences, Triangle Park, North Carolina 27709, and 4Max-Planck-Institut für Biophysikalische Chemie, D-37707 Göttingen, Germany

Metabolism: clinical and experimental, Jan 23, 2018

Heterozygous inactivating mutations in GCK are associated with defects in pancreatic insulin secr... more Heterozygous inactivating mutations in GCK are associated with defects in pancreatic insulin secretion and/or hepatic glycogen synthesis leading to mild chronic hyperglycemia of maturity onset diabetes of young type 2 (MODY2). However, the effect of naturally occurring GCK mutations on the pathogenesis for MODY2 hyperglycemia remains largely unclear, especially in the Asian population. The aim of this study is to explore the potential pathogenicity of novel GCK mutations related to MODY2. Genetic screening for GCK mutations from 96 classical MODY families was performed, and structure-function characterization and clinical profile of identified GCK mutations were conducted. Five novel (F195S, I211T, V222D, E236G and K458R) and five known (T49 N, I159V, R186X, A188T and M381 T) mutations were identified and co-segregated with hyperglycaemia in their pedigrees. R186X generates non-functional truncated form and V222D and E236G fully inactivate glucokinase due to severe structure disrupt...