Androgen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3'-triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidences show a higher incidence of PCa in men with elevated thyroid hormone levels. The thyroid hormone binding protein μ-Crystallin (CRYM) mediates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TRα/TRβ) in target tissues. We show in our study that low CRYM expression levels in PCa patients are associated with early biochemical recurrence and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intracellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in positron emission tomography/magnetic resonance imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3- and androgen-mediated signaling in PCa. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth.
- MeSH
- androgenní receptory genetika metabolismus MeSH
- buňky PC-3 MeSH
- cholin aplikace a dávkování analogy a deriváty MeSH
- čipová analýza tkání MeSH
- down regulace * MeSH
- kohortové studie MeSH
- krystaliny genetika metabolismus MeSH
- lidé MeSH
- metabolomika MeSH
- nádorové buněčné linie MeSH
- nádory prostaty diagnostické zobrazování genetika metabolismus patologie MeSH
- PET/CT MeSH
- prognóza MeSH
- receptory thyreoidních hormonů genetika MeSH
- regulace genové exprese u nádorů MeSH
- sekvenční analýza RNA MeSH
- signální transdukce * MeSH
- staging nádorů MeSH
- stanovení celkové genové exprese MeSH
- trijodthyronin antagonisté a inhibitory metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The Wnt/β-catenin signaling pathway controls many processes during development, including cell proliferation, cell differentiation and tissue homeostasis, and its aberrant regulation has been linked to various pathologies. In this study we investigated the effect of ectopic activation of Wnt/β-catenin signaling during lens fiber cell differentiation. To activate Wnt/β-catenin signaling in lens fiber cells, the transgenic mouse referred to as αA-CLEF was generated, in which the transactivation domain of β-catenin was fused to the DNA-binding protein LEF1, and expression of the transgene was controlled by αA-crystallin promoter. Constitutive activation of Wnt/β-catenin signaling in lens fiber cells of αA-CLEF mice resulted in abnormal and delayed fiber cell differentiation. Moreover, adult αA-CLEF mice developed cataract, microphthalmia and manifested downregulated levels of γ-crystallins in lenses. We provide evidence of aberrant expression of cell cycle regulators in embryonic lenses of αA-CLEF transgenic mice resulting in the delay in cell cycle exit and in the shift of fiber cell differentiation to the central fiber cell compartment. Our results indicate that precise regulation of the Wnt/β-catenin signaling activity during later stages of lens development is essential for proper lens fiber cell differentiation and lens transparency.
- MeSH
- beta-katenin genetika metabolismus MeSH
- buněčná diferenciace genetika MeSH
- buněčný cyklus genetika MeSH
- DNA vazebné proteiny genetika metabolismus MeSH
- epitelové buňky metabolismus MeSH
- katarakta genetika metabolismus MeSH
- krystaliny genetika metabolismus MeSH
- lidé MeSH
- mikroftalmie genetika metabolismus MeSH
- myši inbrední C57BL MeSH
- myši transgenní genetika metabolismus MeSH
- myši MeSH
- oční čočka metabolismus MeSH
- promotorové oblasti (genetika) genetika MeSH
- signální dráha Wnt genetika MeSH
- signální transdukce genetika MeSH
- transkripční faktor LEF-1 MeSH
- vývojová regulace genové exprese MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Lens-containing eyes are a feature of surprisingly broad spectrum of organisms across the animal kingdom that represent a significant improvement of simple eye composed of just photoreceptor cells and pigment cells. It is apparent that such an upgrade of animal visual system has originated numerous times during evolution since many distinct strategies to enhance light refraction through the use of lens and cornea have been utilized. In addition to having an ancient role in prototypical eye formation Pax transcription factors were convergently recruited for regulation of structurally diverse crystallins and genes affecting morphogenesis of various lens-containing eyes.
- MeSH
- biodiverzita MeSH
- biologická evoluce MeSH
- biologické modely MeSH
- financování organizované MeSH
- fylogeneze MeSH
- krystaliny genetika metabolismus MeSH
- oči - fyziologické jevy MeSH
- oční čočka fyziologie metabolismus MeSH
- regulace genové exprese MeSH
- regulační oblasti nukleových kyselin fyziologie MeSH
- rohovka fyziologie MeSH
- transkripční faktory paired box genetika MeSH
- životní prostředí MeSH
- zrak fyziologie genetika MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
Cnidaria is the earliest-branching metazoan phylum containing a well-developed, lens-containing visual system located on specialized sensory structures called rhopalia. Each rhopalium in a cubozoan jellyfish Tripedalia cystophora has a large and a small complex, camera-type eye with a cellular lens containing distinct families of crystallins. Here, we have characterized J2-crystallin and its gene in T. cystophora. The J2-crystallin gene is composed of a single exon and encodes a 157-amino acid cytoplasmic protein with no apparent homology to known proteins from other species. The non-lens expression of J2-crystallin suggests nonoptical as well as crystallin functions consistent with the gene-sharing strategy that has been used during evolution of lens crystallins in other invertebrates and vertebrates. Although nonfunctional in transfected mammalian lens cells, the J2-crystallin promoter is activated by the jellyfish paired domain transcription factor PaxB in co-transfection tests via binding to three paired domain sites. PaxB paired domain-binding sites were also identified in the PaxB-regulated promoters of the J1A- and J1B-crystallin genes, which are not homologous to the J2-crystallin gene. Taken together with previous studies on the regulation of the diverse crystallin genes, the present report strongly supports the idea that crystallin recruitment of multifunctional proteins was driven by convergent changes involving Pax (as well as other transcription factors) in the promoters of nonhomologous genes within and between species as well as within gene families.
- MeSH
- buněčné linie MeSH
- Cercopithecus aethiops MeSH
- COS buňky MeSH
- Cubozoa genetika metabolismus MeSH
- cytoplazma metabolismus MeSH
- exony MeSH
- financování organizované MeSH
- klonování DNA MeSH
- krystaliny genetika chemie metabolismus MeSH
- lidé MeSH
- molekulární evoluce MeSH
- molekulární sekvence - údaje MeSH
- oční čočka metabolismus MeSH
- promotorové oblasti (genetika) MeSH
- regulace genové exprese MeSH
- sekvence nukleotidů MeSH
- transkripční faktory paired box genetika metabolismus metabolismus MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- MeSH
- dítě MeSH
- heterozygot MeSH
- katarakta patologie vrozené MeSH
- konformace proteinů genetika MeSH
- krystaliny genetika chemie MeSH
- lidé MeSH
- methionin genetika nedostatek MeSH
- oční čočka chemie patologie MeSH
- předškolní dítě MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- Publikační typ
- kazuistiky MeSH
- MeSH
- alkalická fosfatasa * genetika MeSH
- antigeny CD45 * genetika MeSH
- druhová specificita MeSH
- geny * MeSH
- inbrední kmeny potkanů MeSH
- inhibiny * genetika MeSH
- křížení genetické MeSH
- krysa rodu rattus * genetika MeSH
- krystaliny * genetika MeSH
- lidé MeSH
- lod skóre MeSH
- mapování chromozomů MeSH
- myši genetika MeSH
- potkani inbrední LEW MeSH
- potkani inbrední SHR MeSH
- proteinfosfatasa 1 MeSH
- renin * genetika MeSH
- sodíko-draslíková ATPasa * genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus * genetika MeSH
- lidé MeSH
- myši genetika MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
