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- Collingwood, T N, et al.
(author)
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A natural transactivation mutation in the thyroid hormone beta receptor: impaired interaction with putative transcriptional mediators.
- 1997
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In: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424. ; 94:1, s. 248-53
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Journal article (peer-reviewed)abstract
- The syndrome of resistance to thyroid hormone is characterized by elevated serum free thyroid hormones, failure to suppress pituitary thyrotropin secretion, and variable peripheral refractoriness to hormone action. Here we describe a novel leucine to valine mutation in codon 454 (L454V) of the thyroid hormone beta receptor (TR beta) in this disorder, resulting in a mutant receptor with unusual functional properties. Although the mutant protein binds ligand comparably to wild-type receptor and forms homo- and heterodimers on direct repeat, everted repeat, or palindromic thyroid response elements, its ability to activate transcription via these elements is markedly impaired. The hydrophobic leucine residue lies within an amphipathic alpha-helix at the carboxyl terminus of TR beta and the position of the homologous residue in the crystal structure of TR alpha indicates that its side chain is solvent-exposed and might interact with other proteins. We find that two putative transcriptional mediators (RIP140 and SRC-1) exhibit hormone-dependent association with wild-type TR. In comparison, the interaction of this natural mutant (L454V) and artificial mutants (L454A, E457A) with RIP140 and SRC-1 is markedly reduced. Furthermore, coexpression of SRC-1 is able to restore the transcriptional activity of the L454V mutant receptor, indicating that the interaction of this residue with accessory proteins is critical for transcriptional activation. Finally, the occurrence of the L454V mutation in resistance to thyroid hormone, together with impaired negative regulation of the thyroid-stimulating hormone alpha promoter by this mutant, suggests that the amphipathic alpha-helix also mediates hormone-dependent transcriptional inhibition, perhaps via interaction with these or other accessory factors.
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| 2. |
- Grage-Griebenow, E., et al.
(author)
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An Fcγ receptor I (CD64)-negative subpopulation of human peripheral blood monocytes is resistant to killing by antigen-activated CD4-positive cytotoxic T cells
- 1997
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In: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 27:9, s. 2358-2365
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Journal article (peer-reviewed)abstract
- It has been demonstrated that in monocyte/T cell co-cultures activated with recall antigens, cytotoxic T cells were generated which are able to reduce the number of antigen-presenting monocytes. In previous studies we could show that a minor subset of monocytes, the Fc gamma receptor I-negative (CD64(-)) monocytes, exhibits significantly higher antigen-presenting capacity than the main population of monocytes (> 90%) which are Fc gamma receptor I-positive (CD64(+)). Therefore, we addressed the question whether they are also differentially susceptible to T cell-mediated killing. In the present study we demonstrate that the CD64(-) monocyte subset is more resistant to killing by antigen-activated T cells than CD64(+) monocytes, as indicated by a higher viability and recovery of CD64(-) monocytes. This mechanism involves CD95 (Fas) antigen, since monocyte death in co-cultures with antigen-activated T cells could be partially reduced by blocking anti-Fas monoclonal antibodies (mAb). In agreement with this finding, although CD95 antigen was expressed on CD64(+) and CD64(-) monocytes at comparable levels, killing of CD64(-) monocytes by activating anti-Fas mAb was lower than of CD64(+) monocytes.
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