Cell-cell adhesion, as mediated by the cadherin-catenin system, is a prerequisite for normal cell function and the preservation of tissue integrity. With recent progress in our understanding, beta-catenin as a component of a complex signal transduction pathway may serve as a common switch in central processes that regulate cellular differentiation and growth. The function of the cadherin-catenin system in cell adhesion as well as in intracellular signaling, appears to be subjected to multifactorial control by a variety of different mechanisms, and data on a hormonal control of these signaling pathways, even though scarce to date, suggest an important regulatory influence in many cellular systems. Loss of E-cadherin-catenin function was described in many tumors along with an increased invasiveness and a decreased prognosis of many carcinomas, including tumors of endocrine glands and their target systems, and a causal role of this loss-of-function in the multifactorial process of tumorigenesis was recently proven in genetic mouse models. Modification of E-caderin-catenin function in endocrine and nonendocrine tumors may involve germline and somatic gene mutations, epigenetic mechanisms such as gene silencing due to promotor-hypermethylation, and posttranscriptional events, likely to be involved in many endocrine tissues and their target organs. Such events may converge on nuclear activation of oncogenes such as c-myc by the beta-catenin/TCF4 complex. The expression and functional status of the components of the cadherin-catenin system may serve as prognostic markers for endocrine and nonendocrine tumors. The frequent involvement of functional dysregulation in many tumors raises hopes that better definition of the regulation of all components of the cadherin-catenin system and their response to extracellular modulators may eventually lead to new therapeutic approaches for these tumors and help to prevent, more specifically, growth, invasion, and metastasis of these carcinomas.
Treatment of six-day-old barley leaves with white light of high intensity, 250-2000 W/m2, leads to a linear increase in the steady-state concentrations of early light-inducible protein (ELIP) mRNA followed by an accumulation of the protein. Accumulation of ELIP mRNA, under light stress, is highest in the basal third of the leaf and declines to approximately 50% of this level in the apical segment. The amount of the accumulated protein decreases more steeply towards the tip than would be expected from mRNA levels. This finding, as well as the fact that during greening a massive accumulation of the protein starts only at a time when the steady-state concentrations of ELIP mRNA have declined to 10% of the maximal value, indicate post-transcriptional control. Accumulation is presumably achieved by stabilization of the protein. ELIP mRNA and protein levels, induced by a 2-h period of high-light stress, are lowest in the afternoon and highest at midnight and during the morning. The inducibility of ELIP by high light is therefore under diurnal control. An increase of light stress, due to application of the carotenoid-biosynthesis inhibitor norfluorazon, results in a considerable induction of ELIP mRNA and protein. The plant hormone abscisic acid exerts only a small effect on the mRNA level. In all cases studied, the light-induced increase in the amount of ELIP mRNA was accompanied by a corresponding decline in the mRNA levels for the apoprotein of the chlorophyll-ah-binding protein. Steady-state concentrations of mRNA for the small subunit of ribulose-l,5-bisphosphate carboxylase were hardly affected under all investigated light intensities.The process of thylakoid formation has been thoroughly investigated and although the principle mechanisms are understood the complete details are not yet known [l]. This is especially true for the various mechanisms which precisely regulate photosynthetic efficiency and which have to take place under natural conditions e.g. adaptation to low-light and high-light intensities and also low and high temperatures. During the process of greening, the coordinated expression of genes has been observed [2]. Among the proteins that appear first during greening are early light-inducible proteins (ELIP). These nuclear-encoded thylakoid-membrane proteins share homology with the apoprotein of the chlorophyll-albbinding protein (LHC 11) [3-51 and with the recently discovered 22-kDa protein of photosystem I1 (psbS) [6, 71. The latter similarity seems important as, in contrast to LHC, the binding of pigments has not been detected for ELIP or psbS.During the last two years, ELIP have been recognized as light-stress proteins [8 -101. These studies, derived from earlier findings, showed that after transport into mature chloroplasts ELIP are found in the vicinity of photosystem I1 and can be crosslinked to the D1 protein [ll]. Since D1 is known to rapidly turn over during high-light stress or photoinhibi- tion [12, 131, the expression of ELIP was studied under conditions of light stress. It was found th...
The sodium/iodide symporter (NIS) has been recognized as an attractive target for radioiodine-mediated cancer gene therapy. In this study we investigated the role of human NIS for cellular uptake of the high LET alpha-emitter astatine-211 ((211)At) in comparison with radioiodine as a potential radionuclide for future applications. A mammalian NIS expression vector was constructed and used to generate six stable NIS-expressing cancer cell lines (three derived from thyroid carcinoma, two from colon carcinoma, one from glioblastoma). Compared with the respective control cell lines, steady state radionuclide uptake of NIS-expressing cell lines increased up to 350-fold for iodine-123 ((123)I), 340-fold for technetium-99m pertechnetate ((99m)TcO(4)(-)) and 60-fold for (211)At. Cellular (211)At accumulation was found to be dependent on extracellular Na(+) ions and displayed a similar sensitivity towards sodium perchlorate inhibition as radioiodide and (99m)TcO(4)(-) uptake. Heterologous competition with unlabelled NaI decreased NIS-mediated (211)At uptake to levels of NIS-negative control cells. Following uptake both radioiodide and (211)At were rapidly (apparent t(1/2) 3-15 min) released by the cells as determined by wash-out experiments. Data of scintigraphic tumour imaging in a xenograft nude mice model of transplanted NIS-modified thyroid cells indicated that radionuclide uptake in NIS-expressing tumours was up to 70 times ((123)I), 25 times ((99m)TcO(4)(-)) and 10 times ((211)At) higher than in control tumours or normal tissues except stomach (3-5 times) and thyroid gland (5-10 times). Thirty-four percent and 14% of the administered activity of (123)I and (211)At, respectively, was found in NIS tumours by region of interest analysis ( n=2). Compared with cell culture experiments, the effective half-life in vivo was greatly prolonged (6.5 h for (123)I, 5.2 h for (211)At) and preliminary dosimetric calculations indicate high tumour absorbed doses (3.5 Gy/MBq(tumour) for (131)I and 50.3 Gy/MBq(tumour) for (211)At). In conclusion, NIS-expressing tumour cell lines of different origin displayed specific radionuclide uptake in vitro and in vivo. We provide first direct evidence that the high-energy alpha-emitter (211)At is efficiently transported by NIS. Application of (211)At may direct higher radiation doses to experimental tumours than those calculated for (131)I. Thus, (211)At may represent a promising alternative radionuclide for future NIS-based tumour therapy.
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