Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast

  title={Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast},
  author={Joseph Heitman and NR Movva and MN Hall},
  pages={905 - 909}
FK506 and rapamycin are related immunosuppressive compounds that block helper T cell activation by interfering with signal transduction. In vitro, both drugs bind and inhibit the FK506-binding protein (FKBP) proline rotamase. Saccharomyces cerevisiae cells treated with rapamycin irreversibly arrested in the G1 phase of the cell cycle. An FKBP-rapamycin complex is concluded to be the toxic agent because (i) strains that lack FKBP proline rotamase, encoded by FPR1, were viable and fully resistant… 

TOR Mutations Confer Rapamycin Resistance by Preventing Interaction with FKBP12-Rapamycin (*)

These studies confirm that the TOR proteins are direct targets of FKBP12-rapamycin, reveal that drug-resistant mutations prevent this association, and define structural features of these complexes.

A mammalian protein targeted by G1-arresting rapamycin–receptor complex

A mammalian FKBP–rapamycin-associated protein (FRAP) is isolate whose binding to structural variants of rapamycin complexed to FK BP12 correlates with the ability of these ligands to inhibit cell-cycle progression.

Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells (*)

The results strongly suggest that the FKBP12-rapamycin complex interacts with homologous ligands in yeast and mammalian cells and that the loss of mTOR function is directly related to the inhibitory effect of rapamycin on G1- to S-phase progression in T-lymphocytes and other sensitive cell types.

The rapamycin-sensitive signal transduction pathway as a target for cancer therapy

CCI-779, an ester analog of rapamycin with improved pharmaceutical properties and aqueous solubility, has demonstrated impressive activity against a broad range of human cancers growing in tissue culture and in human tumor xenograft models, which has supported the development of compounds targetingRapamycin-sensitive signal-transduction pathways.

Rapamycin resistance tied to defective regulation of p27Kip1

The ability to regulate p27Kip1 levels is important for rapamycin to exert its antiproliferative effects, which are associated with prevention of mitogen-induced downregulation of the cyclin-dependent kinase inhibitor p27 Kip1, suggesting that the latter may play an important role in the growth pathway targeted by rapamyzin.

Yeast as model T cells

The challenges ahead are to understand the normal cellular roles of the immunophilins, to biochemically define the direct target of the FKBP12-rapamycin complex, and to translate recent advances into the design of novel immunosuppressants.

Rapamycin Blocks Sexual Development in Fission Yeast through Inhibition of the Cellular Function of an FKBP12 Homolog*

It is shown that disruption of the S. pombe FKBP12 homolog,fkh1 +, at its chromosomal locus results in a mating-deficient phenotype that is highly similar to that obtained by treatment of wild type cells with rapamycin.

Large FK506-Binding Proteins Shape the Pharmacology of Rapamycin

It is shown that rapamycin complexes of larger FKBP family members can tightly bind to mTOR and potently inhibit its kinase activity, providing a mechanistic rationale for preferential mTOR inhibition in specific cell or tissue types by engaging specific FK BP homologs.

Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase

The selective blockade of the p70 S6 kinase activation cascade by the rapamycin–FKBP complex implicates this signalling pathway in the regulation of T cell entry into S phase.



FK 506-binding protein proline rotamase is a target for the immunosuppressive agent FK 506 in Saccharomyces cerevisiae.

Experiments described here demonstrate genetically that FKBP is a target for FK 506 in vivo, and isolates the gene encoding the FK BP proline rotamase (FPR1) from Saccharomyces cerevisiae, which is highly homologous with bovine and human FkBP and shares no homology with cyclophilin.

Suppression of B cell activation by cyclosporin A, FK506 and rapamycin

Comparisons of the effects of the immunosuppressants cyclosporin A, FK506 and rapamycin using murine B cells activated with a variety of mitogens suggest that although CsA, F k506 andRapamycin are all inhibitors of B cell activation, the inhibitory activity of rapamyccin can be clearly distinguished from that of Cs a and Fk506.

Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin.

It is suggested that immunophilin bound to FK506 interferes with antigen receptor-induced signals, while rapamycin bound to the Immunosuppressant binding proteinInterference with IL-2- induced signals is suggested.

Molecular cloning and overexpression of the human FK506-binding protein FKBP

The complementary DNA and derived amino-acid sequences of human FKBP from Jurkat cells and also the efficient overexpression in Escherichia coli of fully active, recombinant human FkBP are reported.

The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells.

FK-506 and RAP antagonize each other's biologic activity and physically interact with a common receptor site in T cells and CsA acts at a site distinct from the cellular target(s) of Fk-506 or RAP.

A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin

CYCLOSPORIN A and the newly discovered immunosuppressant, FK-506, are potent inhibitors of T cell activation1. In addition to their clinical importance in the prevention of allograft rejection,

Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin.

FK-506 and CsA alter similar calcium-associated events of T cell activation and block T cell proliferation primarily by suppressing lymphokine production, and RAP interferes with a different set of events and inhibits T cells by impairing their response to growth-promoting lymphokines.

The actions of cyclosporin A and FK506 suggest a novel step in the activation of T lymphocytes.

Using constructs in which mRNA production controlled by a specific transcription factor could be readily measured, it was found that both cyclosporin A and FK506 completely inhibited transcription activated by NF‐AT,NFIL2 A, NFIL2 B and partially inhibited transcriptionactivated by NF kappa B, indicating that only a subset of signalling pathways regulated by Ca2+ is sensitive to these drugs.

Cyclosporin A inhibits T-cell growth factor gene expression at the level of mRNA transcription.

Data suggest a relatively selective action of CsA on TCGF gene transcription, which is at least in part due to inhibition of lymphokine production by activated T lymphocytes.

FKBl encodes a nonessential FK 506-binding protein in Saccharomyces cerevisiae and contains regions suggesting homology to the cyclophilins

A search of translated nucleic acid data bases revealed bacterial FKBP homologs in Neisseria meningiditis and Pseudomonas aeruginosa and revealed a region of similarity that is speculated to be a homologous domain related to the functional similarities of the two proteins.