Evidence for a functional receptor for cyclosporin A on the surface of lymphocytes.

Cacalano, Nicholas A.; Chen, B X; Cleveland, William L.; Erlanger, Bernard F.

doi:10.1073/pnas.89.10.4353

Cited by 31 publications

(14 citation statements)

References 41 publications

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“…In addition, the observation that CsA does not have a significant effect upon the mobilization of Ca z÷ by ionomycin within the cell, as measured in Fluo-3/AM-labelled cells, suggests that the mode of action of the ionomycin-induced inhibition is likely to be the result of a CsA-suppressible T cell activation event(s). Protein-bound CsA, which is unable to enter the cell, can mediate an inhibition of T cell activation in a way similar to uncomplexed CsA (Cacalano et aL, 1992). If CsA is able to act at the cell surface, then this activity may stimulate a different activation pathway to which the HTLV-1 LTR is responsive.…”

Section: Discussionmentioning

confidence: 99%

Calcium-mediated inhibition of phorbol ester and Tax trans-activation of the human T cell leukaemia virus type 1

Copeland

Haaksma

Goudsmit

et al. 1994

Journal of General Virology

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Human Jurkat T cells containing a stably integrated human T cell leukaemia virus type 1 (HTLV-1) long terminal repeat (LTR) reporter gene construct were used to study the role of calcium-dependent cellular activation pathways in LTR trans-activation. Treatment of these cells with the calcium ionophore ionomycin resulted in a reduced basal response of the LTR and reduced responses to 12-O-tetradecanoylphorbol-13-acetate-and Tax-mediated trans-activation. This effect was also observed for virus production in the HTLV-1-producing T cell line MT-2. Experiments designed to determine the events underlying this inhibition, using inhibitors of calcium-related events, revealed that the ionomycininduced repression of the LTR was alleviated in all cases by cyclosporin A. This compound was also effective in preventing the ionomycin-induced reduction in virus production in MT-2 cells. These results suggest a role for calcium-related events in the down-regulation of HTLV-1 expression.

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Section: Discussionmentioning

confidence: 99%

Calcium-mediated inhibition of phorbol ester and Tax trans-activation of the human T cell leukaemia virus type 1

Copeland

Haaksma

Goudsmit

et al. 1994

Journal of General Virology

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“…Mitochondrial and plasma membrane cyclophilins have also been described (19,20). Finally, CsA receptors have been reported on the surface of lymphocytes (21). Thus the cyclophilins function in many compartments of the cell.…”

mentioning

confidence: 95%

Cyclophilin B trafficking through the secretory pathway is altered by binding of cyclosporin A.

Price

Jin

Lim

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

113

103

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Cyclophilin B is targeted to the secretory pathway via an endoplasmic reticulum signal sequence. We analyzed the localization and trafficking of endogenous and transfected cyclophilin B in mammalian cells. Cyclophilin B accumulates both in the endoplasmic reticulum and in complexes on the plasma membrane. The immunosuppressant cyclosporin A specifically mobilizes cyclophilin B from the endoplasmic reticulum, and promotes the secretion of cyclophilin B into the medium. We suggest that cyclosporin A competes with endogenous plasma membrane proteins for association with cyclophilin B in the secretory pathway. These findings argue in favor ofa role for cyclophilin B as a chaperone to proteins destined for the plasma membrane, rather than solely as a proline isomerase functioning within the endoplasmic reticulum.

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“…This step presumably blocks dephosphorylation of the NT-ATc or another protein which interacts with the NT-ATc and restricts it to the cytosol. Alternatively a surfaceanchored immunophilin (shaded ellipsoid) could be responsible for the immunosuppressive effects of CsA (Calcalano et al, 1992) by blocking another kinase or phosphatase which interacts with NFATc or OAP.…”

Section: Nuclear Events Controlled By Fk506 and Csamentioning

confidence: 99%

Peptidylproline cis‐trans‐isomerases: immunophilins

Gałat

1993

European Journal of Biochemistry

338

184

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Two sequence-unrelated families of proteins possess peptidylproline cis-trans-isomerase activities (PPIase). PPIases are highly sequence conserved and multifunctional proteins which are present in many types of cells with a considerably divergent phylogenetic distribution. On the cellular level, PPIases occur in every compartment, both as free species and anchored to membranes. Diverse posttranslational modifications such as glycosylation, N-terminal modifications and phosphorylation constitute the additional functional features of PPIases. Folding, assembly and trafficking of proteins in the cellular milieu are regulated by PPIases. These enzymes accelerate the rate of in-vitro protein folding and they have the ability to bind proteins and act as chaperones. Some PPIases are coregulatory subunits of molecular complexes including heat-shock proteins, glucocorticoid receptors and ion channels. Secreted forms of PPIases are inflammatory and chemotactic agents for monocytes, eosinophils and basophils. The potent and clinically useful immunosuppressants CsA, FK.506 or rapamycin bind with high affinities to PPIases (immunophilins). The binding criterion allows us to sort the PPIases for the following two superfamilies of proteins : the cyclophilins (CsA-binding proteins) and the FKBP (FK.506/rapamycin-binding proteins).Although none of PPIases appeared to be essential for the viability of haploid yeast cells some of the immunophilidimmunosuppressant complexes are toxic both for yeast and mammalian cells. At least seven unlinked genes of cyclophilins and four unlinked genes of FKBP exist in human genomic DNA. Selected immunophilins regulate two different signalling pathways in lymphoid cells, namely the secretion of growth factors by stimulated T-cells and interleukin-2-induced T-cell proliferation. Moreover, selected FKBP mediate the cytotoxic effects of rapamycin in non-lymphoid cells. Accounts of the discovery of PPIases (immunophilins) and their functions are given in this review. A larger spectrum of proteins is analysed in relation to various signal-transduction pathways in lymphoid cells which involve immunophilins or their complexes with the immunosuppressants CsA, FK.506 or rapamycin.

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Evidence for a functional receptor for cyclosporin A on the surface of lymphocytes.

Cited by 31 publications

References 41 publications

Calcium-mediated inhibition of phorbol ester and Tax trans-activation of the human T cell leukaemia virus type 1

Calcium-mediated inhibition of phorbol ester and Tax trans-activation of the human T cell leukaemia virus type 1

Cyclophilin B trafficking through the secretory pathway is altered by binding of cyclosporin A.

Peptidylproline cis‐trans‐isomerases: immunophilins

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