Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay

BACKGROUND: Congenital forms of hearing impairment can be caused by mutations in the estrogen related receptor beta (ESRRB) gene. Our initial linkage studies suggested the ESRRB locus is linked to high caries experience in humans. METHODS: We tested for association between the ESRRB locus and dental caries in 1,731 subjects, if ESRRB was expressed in whole saliva, if ESRRB was associated with the microhardness of the dental enamel, and if ESRRB was expressed during enamel development of mice. RESULTS: Two families with recessive ESRRB mutations and DFNB35 hearing impairment showed more extensive dental destruction by caries. Expression levels of ESRRB in whole saliva samples showed differences depending on sex and dental caries experience. CONCLUSIONS: The common etiology of dental caries and hearing impairment provides a venue to assist in the identification of individuals at risk to either condition and provides options for the development of new caries prevention strategies, if the associated ESRRB genetic variants are correlated with efficacy.Fil: Weber, Megan L.. University of Pittsburgh; Estados UnidosFil: Hsin, Hong Yuan. University of Pittsburgh; Estados UnidosFil: Kalay, Ersan. Karadeniz Technical University; TurquíaFil: Brožková, Dana Š. Charles University; República Checa. University Hospital Motol; República ChecaFil: Shimizu, Takehiko. Nihon University. School of Dentistry; JapónFil: Bayram, Merve. Medipol Istanbul University; TurquíaFil: Deeley, Kathleen. University of Pittsburgh; Estados UnidosFil: Küchler, Erika C.. University of Pittsburgh; Estados UnidosFil: Forella, Jessalyn. University of Pittsburgh; Estados UnidosFil: Ruff, Timothy D.. University of Pittsburgh; Estados UnidosFil: Trombetta, Vanessa M.. University of Pittsburgh; Estados UnidosFil: Sencak, Regina C.. University of Pittsburgh; Estados UnidosFil: Hummel, Michael. University of Pittsburgh; Estados UnidosFil: Briseño Ruiz, Jessica. University of Pittsburgh; Estados UnidosFil: Revu, Shankar K.. University of Pittsburgh; Estados UnidosFil: Granjeiro, José M.. Universidade Federal Fluminense; BrasilFil: Antunes, Leonardo S.. Universidade Federal Fluminense; BrasilFil: Antunes, Livia A.. Universidade Federal Fluminense; BrasilFil: Abreu, Fernanda V.. Universidade Federal Fluminense; BrasilFil: Costabel, Marcelo C.. Universidade Federal do Rio de Janeiro; BrasilFil: Tannure, Patricia N.. Veiga de Almeida University; Brasil. Salgado de Oliveira University; BrasilFil: Koruyucu, Mine. Istanbul University; TurquíaFil: Patir, Asli. Medipol Istanbul University; TurquíaFil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mereb, Juan C.. Estudio Colaborativo Latino Americano de Malformaciones Congénitas; ArgentinaFil: Castilla, Eduardo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Orioli, Iêda M.. Universidade Federal do Rio de Janeiro; BrasilFil: Marazita, Mary L.. University of Pittsburgh; Estados UnidosFil: Ouyang, Hongjiao. University of Pittsburgh; Estados UnidosFil: Jayaraman, Thottala. University of Pittsburgh; Estados UnidosFil: Seymen, Figen. Istanbul University; TurquíaFil: Vieira, Alexandre R.. University of Pittsburgh; Estados Unido

Parathyroid hormone -related protein regulates cementogenesis.

Parathyroid hormone-related protein (PTHrP) plays an essential role in the development and homeostasis of many tissues/organs. This dissertation is aimed at exploring the role of PTHrP in regulating cementum formation. Initially, two parent cementoblast cell populations (SV-CM/PDL and OC-CM) were established. The SV-CM/PDL population contains both cementoblasts and periodontal ligament (PDL) cells obtained from the root surface of the first mandibular molars of CD-1 mice and immortalized with SV-40 T antigen (TAg). The OC-CM population contains cementoblasts exclusively and was established from OC-TAg transgenic mice whose cells harbor an osteocalcin promoter-driving TAg gene, TAg. To identify the cell targets for PTHrP action, clonal populations were established from the SV-CM/PDL and the OC-CM populations. Cementoblast subclones were defined cells expressing BSP and/or OCN transcripts, while PDL cell lines were designated cells lacking BSP and OCN mRNA. Cementoblasts were cuboidal and promoted biomineralization both in vitro and in vivo. In contrast, PDL subclones were spindle-shaped and failed to promote mineralized nodule formation both in vitro and in vivo. The effect of PTHrP on clonal populations was determined. Cementoblasts, but not PDL cells, expressed PTH-1 receptor mRNA and exhibited PTHrP-mediated elevation in cAMP levels and c-fos gene induction. PTHrP reduced BSP and OCN mRNA expression and blocked cementoblast-mediated mineralization in vitro. Collectively, these data strongly suggest that cementoblasts are targets for PTHrP in vivo and that PTHrP plays an inhibitory role in regulating cementoblast activities during cementogenesis. Having identified the cell target of PTHrP and determined the effects of PTHrP the molecular mechanisms underlying PTHrP regulation, focusing on PTHrP effect on BSP gene expression in cementoblasts, was investigated. Results demonstrated that long-term exposure of cementoblasts to PTHrP repressed gene expression and protein synthesis of BSP, in vitro. Further, PTHrP inhibition of BSP gene expression was dependent on transcription and protein synthesis. The inhibitory effect of PTHrP was mediated primarily via activation of the cAMP/PKA pathway, while the PKC pathway was ineffective in mediating the inhibitory actions of PTHrP. These data provide new insights into molecular mechanisms by which PTHrP regulates expression of genes associated with cementum formation.Ph.D.Biological SciencesCellular biologyDentistryHealth and Environmental SciencesMolecular biologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/132436/2/9963861.pd

Signaling by Target of Rapamycin Proteins in Cell Growth Control

Target of rapamycin (TOR) proteins are members of the phosphatidylinositol kinase-related kinase (PIKK) family and are highly conserved from yeast to mammals. TOR proteins integrate signals from growth factors, nutrients, stress, and cellular energy levels to control cell growth. The ribosomal S6 kinase 1 (S6K) and eukaryotic initiation factor 4E binding protein 1(4EBP1) are two cellular targets of TOR kinase activity and are known to mediate TOR function in translational control in mammalian cells. However, the precise molecular mechanism of TOR regulation is not completely understood. One of the recent breakthrough studies in TOR signaling resulted in the identification of the tuberous sclerosis complex gene products, TSC1 and TSC2, as negative regulators for TOR signaling. Furthermore, the discovery that the small GTPase Rheb is a direct downstream target of TSC1-TSC2 and a positive regulator of the TOR function has significantly advanced our understanding of the molecular mechanism of TOR activation. Here we review the current understanding of the regulation of TOR signaling and discuss its function as a signaling nexus to control cell growth during normal development and tumorigenesis

Thermodynamic Properties of Polymorphs of 2,2′-Thiodiethylene Bis[3-(3,5-di-<i>tert</i>-butyl-4-hydroxyphenyl)propionate]

In this work, two polymorphic forms of 2,2′-thiodiethylene bis­[3-(3,5-di<i>tert</i>-butyl-4-hydroxyphenyl)­propionate] (abbreviated as TBHP) were successfully isolated, identified, and characterized by using powder X-ray diffraction and differential scanning calorimetry. It was found that form I has a lower melting temperature than form II. The solubility data of both form I and form II of TBHP in six pure solvents were experimentally measured in the temperature range of (283.15 to 318.15) K at atmospheric pressure by using a dynamic method. For all of the tested solvents, the solubility data of TBHP form I are higher than those of form II. The modified Apelblat equation was used to correlate the solubility of TBHP form I and form II. The mixing Gibbs energy, the mixing enthalpy, and the mixing entropy of both forms were also determined. It was also found that mixing processes of both forms are endothermic, entropy-driven, and spontaneous. Combining the DCS data and all of the thermodynamic data, it was concluded that the relationship between form I and form II of TBHP is monotropic