Disease relevance of Ppia

• Here we present evidence supporting a role for viral-associated CyPA in the early events of HIV-1 infection [1].
• More recently, host-derived cyclophilin A (CyPA) has been shown to be incorporated into HIV-1 virions and its incorporation essential for viral infectivity [1].
• Collectively, our data reveal that a novel function of CypA is required in the processing of RA-induced neuronal differentiation in p19 embryonal carcinoma cells [2].
• Elucidation of the precise role of CypA in these pathways may lead to new targeted therapies for lung cancer [3].
• We recently identified CD147 as the main signaling receptor for cyclophilin A. In the current study we examined the contribution of cyclophilin-CD147 interactions to inflammatory responses in vivo using a mouse model of acute lung injury [4].

High impact information on Ppia

• To identify the native function of CypA, long suspected of regulating signal transduction, we generated mice lacking the Ppia gene [5].
• Thus, CypA inhibits CD4+ T cell signal transduction in the absence of cyclosporine via a regulatory proline residue in Itk [5].
• Cyclophilin A regulates TCR signal strength in CD4+ T cells via a proline-directed conformational switch in Itk [5].
• We measured the mRNA levels of CD68, a macrophage-specific marker, alpha-actin, a smooth muscle cell marker, and cyclophilin A, a control gene [6].
• We report that HIV-1 infection of primary peripheral blood mononuclear cells can be inhibited by: (i) an excess of exogenously added CyPA; (ii) a CsA analogue unable to enter the cells; (iii) neutralizing antibodies to CyPA [1].

Biological context of Ppia

• Ppia was isolated using a PCR screen that distinguishes the expressed gene from multiple pseudogenes present in the mouse genome. mPpia consists of 5 exons and 4 introns spanning roughly 4.5 kb and maps to chromosome 11 near the centromere [7].
• One novel quinoxaline derivative as a potent human cyclophilin A inhibitor shows highly inhibitory activity against mouse spleen cell proliferation [8].
• Cyclophilin-A is a zinc-dependent DNA binding protein in macrophages [9].
• Isolation, characterization and targeted disruption of mouse ppia: cyclophilin A is not essential for mammalian cell viability [7].
• One of the reactive clones was determined by sequence analysis to encode a protein homologous to cyclophilins of other species, in particular cyclophilin A. The 0.8-kb cDNA clone contained an open reading frame of 483 nucleotides which corresponds to a translation product of 161 amino acids with a deduced molecular size of 17.7 kDa [10].

Anatomical context of Ppia

• The binding of CsA to CyPC is similar to that of CsA to human T-cell cyclophilin A (CyPA) [11].
• Thus, we conclude that CyP-A associates in vitro and in vivo with the dynein/dynactin motor protein complex and we suggest that CyP-A may perform a general function related to the binding of cargo for retrograde movement along microtubules [12].
• Here, we show that CyP-A exists in native heterocomplexes containing cytoplasmic dynein that can be formed in cell-free systems [12].
• CyP-A heterocomplexes containing tubulin and dynein can be formed in cytosol prepared under microtubule-stabilizing conditions, and CyP-A colocalizes in mouse fibroblasts with microtubules [12].
• Immunofluorescence microscopy of mouse macrophages cell line with a monoclonal antibody mAb7F1 raised against CypA shows a co-localisation of CypA in the nucleus and in the cytosol [9].

Associations of Ppia with chemical compounds

• Immunosuppressive doses of cyclosporine failed to block the responses of Ppia(-/-) mice to allogeneic challenge [13].
• Although cyclophilin A (CyP-A) is a relatively abundant small immunophilin present in the cytoplasm of all mammalian cells, its general function(s) in the absence of the immunosuppressant drug cyclosporin A is not known [12].
• Stable transfectants with expression of small interfering RNA for targeting cyclophilin A (CypA) in p19 cells lose their potential for retinoic acid (RA)-induced neuronal differentiation but not Me(2)SO-induced mesodermal differentiation [2].
• The founding member of the family, cyclophilin A (CyPA), is an abundant, ubiquitously expressed protein of unknown function that binds with nanomolar affinity to CsA [7].
• Nuclear CypA binds to DNA in a zinc ion-dependent manner, in contrast to recombinant CypB [9].

Physical interactions of Ppia

• However, the conformation of CsA when bound to CyPC is significantly different from that when bound to CyPA [11].

Regulatory relationships of Ppia

• CypA accumulated within the nuclei of damaged neurons after HI, and this nuclear translocation of CypA was suppressed in AIF-deficient harlequin mice [14].

Other interactions of Ppia

• Rag2(-/-) mice reconstituted with Ppia(-/-) splenocytes were also cyclosporine resistant, indicating that this property is intrinsic to Ppia(-/-) immune cells [13].
• Mutation of a conformationally heterogeneous proline in the SH2 domain of Itk disrupted interaction with CypA and specifically increased Th2 cytokine production from wild-type CD4+ T cells [5].
• Cyclophilin A is required for retinoic acid-induced neuronal differentiation in p19 cells [2].
• No changes in mRNA levels were detected for c-myc, TGFbeta1, TGFbeta2, cyclophilin A, or actin [15].
• Myoblasts and myotubes of C2-C12 cells express similar amounts of cyclophilin A and FKBP12, immunophilins known to be intracellular-binding targets for CsA and tacrolimus, respectively [16].

Analytical, diagnostic and therapeutic context of Ppia

• Both copies of Ppia were disrupted in murine embryonic stem (ES) cells via gene targeting [7].
• Cyclophilin A-deficient mice are resistant to immunosuppression by cyclosporine [13].
• By using the surface plasmon resonance (SPR) and fluorescence titration techniques, the kinetic analysis of CypA/DC838 interaction was quantitatively performed [8].
• Localization of cyclophilin A and cyclophilin C mRNA in murine kidney using RT-PCR [17].
• To determine the role of CypA in oncogenesis, stable RNA interference (RNAi)-mediated knockdown of CypA was established in two non-small-cell lung cancer cell lines (ADLC-5M2 and LC-103H), and these cells were grown as xenografts in severe combined immunodeficient mice [3].

References