Transforming growth factor-beta are cytokines with a wide range of biological effects. They play a pathologic role in inflammatory and fibrosing diseases such as nephrosclerosis. TGF-beta s are secreted in a latent form due to noncovalent association with latency associated peptide (LAP), which is a homodimer formed from the propeptide region of TGF-beta. LAP is disulfide linked to another protein, latent TGF-beta binding protein (LTBP). LTBP has features in common with extracellular matrix proteins, and targets latent TGF-beta to the matrix. Activation of latent TGF-beta can be accomplished in vitro by denaturing treatments, plasmin digestion, ionizing radiation and interaction with thrombospondin. The mechanisms by which latent TGF-beta is activated physiologically are not well understood. Results to date suggest an important role for proteases, particularly plasmin, although other mechanisms probably exist. A general model of activation is proposed in which latent TGF-beta is released from the extracellular matrix by proteases, localized to cell surfaces, and activated by cell-associated plasmin.
Dopaminergic (DA) neurons of substantia nigra in the midbrain control voluntary movement, and their degeneration is the cause of Parkinson's disease. The complete set of genes required to specifically determine the development of midbrain DA subgroups is not known yet. We report here that mice lacking the bicoidrelated homeoprotein Pitx3 fail to develop DA neurons of the substantia nigra. Other mesencephalic DA neurons of the ventral tegmental area and retrorubral field are unaltered in their dopamine expression and histological organization. These data suggest that Pitx3-dependent gene expression is specifically required for the differentiation of DA progenitors within the mesencephalic DA system. M idbrain dopaminergic (DA) cells contribute to the control of voluntary movement, cognition, and emotional behavior. Degeneration of these cells results in Parkinson's disease, and aberrant dopamine neurotransmitter signaling is implicated in schizophrenia and addictive behavioral disorders (1-3). Within the midbrain there are three subgroups of DA neurons, the ventral tegmental area (VTA͞A10), substantia nigra (SN͞ A9), and retrorubral field (RRF͞A8), that together constitute the mesencephalic (mes) system (4). Those DA cells in the SN that innervate the striatum preferentially degenerate in Parkinson's disease, whereas other DA subgroups regulate emotional and reward behaviors.Transcription factors regulate the differentiation of midbrain DA neuron precursors. Two transcription factors have been shown to contribute to different aspects of mesDA neuronal differentiation. One of these, the orphan nuclear hormone receptor Nurr1, is required for maturation of mesDA neuron precursors. Mice harboring null alleles of Nurr1 do not express tyrosine hydroxylase (TH), which catalyzes the initial step of dopamine neurotransmitter biosynthesis (5-11). The other factor, LIM homeodomain transcription factor Lmx1b, contributes partially to the specification of mesDA neuronal progenitors beginning on embryonic day 12.5 in the mouse but is not essential for TH gene expression (12).A third transcription factor, the bicoid-related homeodomain-containing transcription factor Pitx3, which is also known as Ptx3, has been implicated in the development of DA neurons. Pitx3 gene expression is restricted to the developing eye and DA progenitor cells from embryonic day 11 throughout adult life in mice (13,14). In the brain, Pitx3 mRNA localizes specifically to the SN and VTA (14). A reduction in Pitx3 mRNA levels is observed in the ventral midbrain of Lmx1b knockout mice, 6-hydroxydopamine-lesioned rats, and Parkinson's patients (8,11,12,14). Yet, Pitx3 expression is maintained in the ventral midbrain of Nurr1 null mutant embryos (12). These data have been interpreted to suggest that Pitx3 contributes to the combinatorial code defined by multiple transcription factors that establish specification and differentiation of midbrain DA progenitors (12). Here we report that Pitx3 is essential for the development of neurons specific to the SN. The D...
Transforming growth factor-β (TGF-β) is secreted by many cell types as part of a large latent complex composed of three subunits: TGF-β, the TGF-β propeptide, and the latent TGF-β binding protein (LTBP). To interact with its cell surface receptors, TGF-β must be released from the latent complex by disrupting noncovalent interactions between mature TGF-β and its propeptide. Previously, we identified LTBP-1 and transglutaminase, a cross-linking enzyme, as reactants involved in the formation of TGF-β. In this study, we demonstrate that LTBP-1 and large latent complex are substrates for transglutaminase. Furthermore, we show that the covalent association between LTBP-1 and the extracellular matrix is transglutaminase dependent, as little LTBP-1 is recovered from matrix digests prepared from cultures treated with transglutaminase inhibitors. Three polyclonal antisera to glutathione S–transferase fusion proteins containing amino, middle, or carboxyl regions of LTBP-1S were used to identify domains of LTBP-1 involved in crosslinking and formation of TGF-β by transglutaminase. Antibodies to the amino and carboxyl regions of LTBP-1S abrogate TGF-β generation by vascular cell cocultures or macrophages. However, only antibodies to the amino-terminal region of LTBP-1 block transglutaminase-dependent cross-linking of large latent complex or LTBP-1. To further identify transglutaminase-reactive domains within the amino-terminal region of LTBP-1S, mutants of LTBP-1S with deletions of either the amino-terminal 293 (ΔN293) or 441 (ΔN441) amino acids were expressed transiently in CHO cells. Analysis of the LTBP-1S content in matrices of transfected CHO cultures revealed that ΔN293 LTBP-1S was matrix associated via a transglutaminasedependent reaction, whereas ΔN441 LTBP-1S was not. This suggests that residues 294–441 are critical to the transglutaminase reactivity of LTBP-1S.
Statin therapy produced significant rapid dose-dependent reductions in FDG uptake that may represent changes in atherosclerotic plaque inflammation. FDG-PET imaging may be useful in detecting early treatment effects in patients at risk or with established atherosclerosis.
Transforming growth factor (TGF-)β is secreted as a latent complex in which the mature growth factor remains associated with its propeptide. In order to elicit a biological response, the cytokine must be released from the latent complex, a process termed latent TGF-β activation or TGF-β formation. Although latent TGF-β activation is a critical step in the regulation of its activity, little is known about the molecular mechanisms that lead to the production of active TGF-β. In this article, we present an overview of the data available on this topic, and we propose a tentative model for the mechanism of TGF-β formation based upon the observations with different cell systems and on recent findings on the structure of the latent TGF-β complex.
In humans, creatinine is formed by a multistep process in liver and muscle and eliminated via the kidney by a combination of glomerular filtration and active transport. Based on current evidence, creatinine can be taken up into renal proximal tubule cells by the basolaterally localized organic cation transporter 2 (OCT2) and the organic anion transporter 2, and effluxed into the urine by the apically localized multidrug and toxin extrusion protein 1 (MATE1) and MATE2K. Druginduced elevation of serum creatinine (SCr) and/or reduced creatinine renal clearance is routinely used as a marker for acute kidney injury. Interpretation of elevated SCr can be complex, because such increases can be reversible and explained by inhibition of renal transporters involved in active secretion of creatinine or other secondary factors, such as diet and disease state. Distinction between these possibilities is important from a drug development perspective, as increases in SCr can result in the termination of otherwise efficacious drug candidates. In this review, we discuss the challenges associated with using creatinine as a marker for kidney damage. Furthermore, to evaluate whether reversible changes in SCr can be predicted prospectively based on in vitro transporter inhibition data, an in-depth in vitro-in vivo correlation (IVIVC) analysis was conducted for 16 drugs with in-house and literature in vitro transporter inhibition data for OCT2, MATE1, and MATE2K, as well as total and unbound maximum plasma concentration (C max and C max,u ) data measured in the clinic.
The vertebrate lens is a relatively simple cellular structure that has evolved to refract light. The ability of the lens to focus light on the retina derives from a number of properties including the expression at high levels of a selection of soluble proteins referred to as the crystallins. In the present study, we have used differential cDNA display techniques to identify a novel, highly abundant and soluble lens protein. Though related to the family of soluble lectins called galectins, it does not bind -galactoside sugars and has atypical sequences at normally conserved regions of the carbohydrate-binding domain. Like some galectin family members, it can form a stable dimer. It is expressed only in the lens and is located at the interface between lens fiber cells despite the apparent lack of any membrane-targeting motifs. This protein is designated GRIFIN (galectin-related inter-fiber protein) to reflect its exclusion from the galectin family given the lack of affinity for -galactosides. Although the abundance, solubility, and lens-specific expression of GRIFIN would argue that it represents a new crystallin, its location at the fiber cell interface might suggest that its primary function is executed at the membrane.
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