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Gene Review

PRF1  -  perforin 1 (pore forming protein)

Homo sapiens

Synonyms: Cytolysin, FLH2, HPLH2, Lymphocyte pore-forming protein, P1, ...
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Disease relevance of PRF1


Psychiatry related information on PRF1

  • This is a complete report of an open trial of manualized psychodynamic psychotherapy for treatment of panic disorder, Panic-Focused Psychodynamic Psychotherapy (PFPP) [6].

High impact information on PRF1

  • Here, we present the first crystal structure of a thiol-activated cytolysin, perfringolysin O, a member of a large family of toxins that kill eukaryotic cells by punching holes in their membranes [7].
  • To test the granule exocytosis model for lymphocyte cytotoxicity, we have expressed the gene for the cytotoxic lymphocyte granule protein cytolysin (perforin) in the noncytotoxic rat basophilic leukemia (RBL) cell line, which undergoes granule exocytosis when its high affinity IgE receptor is cross-linked [8].
  • RBL-cy cells did not lyse non-IgE-coated RBCs copelleted with targets: this sparing of "innocent bystanders" parallels cytotoxic T lymphocyte lysis and suggests a polarized secretion of cytolysin [8].
  • A noncytotoxic mast cell tumor line exhibits potent IgE-dependent cytotoxicity after transfection with the cytolysin/perforin gene [8].
  • Homogenates of RBL-cytolysin (RBL-cy) transfectants showed a calcium-dependent hemolytic activity in dense granule fractions, demonstrating that the expressed cytolysin protein was correctly targeted to secretory granules [8].

Chemical compound and disease context of PRF1

  • The human glutathione S-transferase P1 protein is phosphorylated and its metabolic function enhanced by the Ser/Thr protein kinases, cAMP-dependent protein kinase and protein kinase C, in glioblastoma cells [9].
  • Using polyacrylamide gel electrophoresis, the viral proteins were identified as derived from the P1 (5' terminal), P2 (middle), or P3 (3' terminal) region of the poliovirus translation unit [10].
  • In the P1 generation, dietary administration of 2.5, 10, and 50 ppm 17 beta-estradiol produced dose-dependent decreases in body weight, body weight gain, food consumption, and food efficiency [11].
  • We found that the widely used fluorescent probes fura-2 and indo-1 could not be used to measure the effect of pyrazine analogs on the cytosolic free calcium ([Ca2+]i) of YAC-1 lymphoma cells treated with the pore-forming protein cytolysin/perforin [12].
  • A two-step purification method using ammonium sulfate precipitation and gel filtration was developed for the purification of a variant of the El Tor hemolysin/cytolysin from supernatant fluids of a Vibrio cholerae non-O1 human isolate (strain 2194c) [13].

Biological context of PRF1

  • The P1 gene including at least 95-bp 3' untranslated region is organized in only three exons: the first exon (97 bp) contains all but four nucleotides of the 5' untranslated region and was determined by primer extension and S1 nuclease mapping [14].
  • The lymphocyte pore-forming protein perforin is essential for maintaining immune homeostasis and for effective defense against intracellular pathogens [15].
  • The 5' flanking regions of P1 [14].
  • In situ hybridization analysis with a human perforin cDNA probe revealed that the human perforin (PFP) gene is located on chromosome 17q11-21 [16].
  • To examine the functional activity of the predicted P1 and P4 promoters, alpha hFR promoter-CAT chimeric plasmids were constructed using sequences flanking exon 1 and exon 4 [17].

Anatomical context of PRF1

  • Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis [18].
  • This PFP could be released from granules during cell killing, followed by its polymerization on target membranes to form large transmembrane pores [19].
  • By analogy, we also constructed a model for this domain in perforin/cytolysin, a pore-forming protein found in the cytoplasmic granules of cytotoxic T-lymphocytes [20].
  • The nonreduced forms of complement components or lymphocyte PFP neither react with these antibodies nor give rise to crossreactive antibodies [21].
  • We observed a 7.5- and 10-fold increase in CAT activity in HeLa cells transiently transfected with the P1 and P4 promoter constructs, respectively [17].

Associations of PRF1 with chemical compounds

  • A substrate containing P1 Asp but lacking P4' Glu was cleaved less efficiently (k(cat)/K(m) 5.3 x 10(4) s(-1) M(-1)) [22].
  • BACKGROUND: Serine proteinase inhibitor (PI)-9 with a reactive center P1 (Glu)-P1' is a natural antagonist of granzyme B and is expressed in high levels in cytotoxic T lymphocytes (CTL) [23].
  • Western blot analysis and protease assays of transfected COS cell lysates against a panel of thiobenzyl ester substrates formally demonstrated that the human Met-ase-1 gene encodes a serine proteinase that specifically hydrolyzes substrates containing a methionine (Met-) side chain at P1 [24].
  • Human CD59 is a receptor for the cholesterol-dependent cytolysin intermedilysin [25].
  • Introduction of the nonphysiological homophenylalanine (Hph) residue at P1 resulted in the best substrate Ala-Hph-AMC for DPPI (k(cat)/K(m)=9,000,000M(-1)s(-1)) [26].

Regulatory relationships of PRF1


Other interactions of PRF1

  • Pharmaceuticals activated stress-response signaling protein kinases (ERK1/2), and induced overexpression of glutathione-S-transferase P1 gene [28].
  • Monospecific polyclonal antibodies to purified C9 and PFP show cross-reactivity, suggesting structural homology between the two molecules [29].
  • Munc13-4 mutations were found in 15 of 30 patients with FHL without PRF1 mutations [30].
  • Using RNase protection assays, we demonstrate that transcripts corresponding to the KB1 and KB4 cDNAs originate from promoters upstream from exon 1 and exon 4, designated P1 and P4, respectively, and that these mRNA isoforms are the most abundant transcripts expressed in KB cells and selected normal tissues (including kidney, lung, and cerebellum) [17].
  • In 1999, perforin gene (PRF1) mutation was identified as a cause of 20-30% of FHL (FHL2) cases [31].

Analytical, diagnostic and therapeutic context of PRF1

  • Molecular cloning and chromosomal assignment of a human perforin (PFP) gene [16].
  • The cDNA of the class I loci P1 and P14 were amplified by RT-PCR and subjected to insert into sequencing vectors [32].
  • The presence of PRF1 genetic abnormality correlated well with the lack of perforin expression as determined by flow cytometry [33].
  • 5' UTRs were determined by primer extension analysis, sequencing PFP cDNA clone PFP-7, ribonuclease protection assays, and amplification of poly(A)+ RNA of cytolytic T lymphocyte using polymerase chain reaction (PCR) [34].
  • Constitutive expression of PFP in PB gamma/delta T cells was also demonstrated by Northern blot analysis [35].


  1. Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions. Ishii, E., Ueda, I., Shirakawa, R., Yamamoto, K., Horiuchi, H., Ohga, S., Furuno, K., Morimoto, A., Imayoshi, M., Ogata, Y., Zaitsu, M., Sako, M., Koike, K., Sakata, A., Takada, H., Hara, T., Imashuku, S., Sasazuki, T., Yasukawa, M. Blood (2005) [Pubmed]
  2. Perforin and granzymes have distinct roles in defensive immunity and immunopathology. van Dommelen, S.L., Sumaria, N., Schreiber, R.D., Scalzo, A.A., Smyth, M.J., Degli-Esposti, M.A. Immunity (2006) [Pubmed]
  3. Cytolysin-mediated translocation (CMT): a functional equivalent of type III secretion in gram-positive bacteria. Madden, J.C., Ruiz, N., Caparon, M. Cell (2001) [Pubmed]
  4. Identification of P1 gene domain containing epitope(s) mediating Mycoplasma pneumoniae cytoadherence. Dallo, S.F., Su, C.J., Horton, J.R., Baseman, J.B. J. Exp. Med. (1988) [Pubmed]
  5. Dissociation of membrane binding and lytic activities of the lymphocyte pore-forming protein (perforin). Young, J.D., Damiano, A., DiNome, M.A., Leong, L.G., Cohn, Z.A. J. Exp. Med. (1987) [Pubmed]
  6. A pilot open trial of brief psychodynamic psychotherapy for panic disorder. Milrod, B., Busch, F., Leon, A.C., Aronson, A., Roiphe, J., Rudden, M., Singer, M., Shapiro, T., Goldman, H., Richter, D., Shear, M.K. The Journal of psychotherapy practice and research. (2001) [Pubmed]
  7. Structure of a cholesterol-binding, thiol-activated cytolysin and a model of its membrane form. Rossjohn, J., Feil, S.C., McKinstry, W.J., Tweten, R.K., Parker, M.W. Cell (1997) [Pubmed]
  8. A noncytotoxic mast cell tumor line exhibits potent IgE-dependent cytotoxicity after transfection with the cytolysin/perforin gene. Shiver, J.W., Henkart, P.A. Cell (1991) [Pubmed]
  9. The human glutathione S-transferase P1 protein is phosphorylated and its metabolic function enhanced by the Ser/Thr protein kinases, cAMP-dependent protein kinase and protein kinase C, in glioblastoma cells. Lo, H.W., Antoun, G.R., Ali-Osman, F. Cancer Res. (2004) [Pubmed]
  10. Lycorine: a eukaryotic termination inhibitor? Vrijsen, R., Vanden Berghe, D.A., Vlietinck, A.J., Boeyé, A. J. Biol. Chem. (1986) [Pubmed]
  11. 90-day feeding and one-generation reproduction study in Crl:CD BR rats with 17 beta-estradiol. Biegel, L.B., Flaws, J.A., Hirshfield, A.N., O'Connor, J.C., Elliott, G.S., Ladics, G.S., Silbergeld, E.K., Van Pelt, C.S., Hurtt, M.E., Cook, J.C., Frame, S.R. Toxicol. Sci. (1998) [Pubmed]
  12. Pyrazine compounds and the measurement of cytosolic Ca2+. Kraut, R.P., Greenberg, A.H., Cragoe, E.J., Bose, R. Anal. Biochem. (1993) [Pubmed]
  13. Two-step purification and partial characterization of a variant of the Vibrio cholerae non-O1 hemolysin. McCardell, B.A., Kothary, M.H., Madden, J.M. FEMS Microbiol. Lett. (1999) [Pubmed]
  14. Structure of the human perforin gene. A simple gene organization with interesting potential regulatory sequences. Lichtenheld, M.G., Podack, E.R. J. Immunol. (1989) [Pubmed]
  15. Calcium-dependent plasma membrane binding and cell lysis by perforin are mediated through its C2 domain: A critical role for aspartate residues 429, 435, 483, and 485 but not 491. Voskoboinik, I., Thia, M.C., Fletcher, J., Ciccone, A., Browne, K., Smyth, M.J., Trapani, J.A. J. Biol. Chem. (2005) [Pubmed]
  16. Molecular cloning and chromosomal assignment of a human perforin (PFP) gene. Shinkai, Y., Yoshida, M.C., Maeda, K., Kobata, T., Maruyama, K., Yodoi, J., Yagita, H., Okumura, K. Immunogenetics (1989) [Pubmed]
  17. The divergent 5' termini of the alpha human folate receptor (hFR) mRNAs originate from two tissue-specific promoters and alternative splicing: characterization of the alpha hFR gene structure. Elwood, P.C., Nachmanoff, K., Saikawa, Y., Page, S.T., Pacheco, P., Roberts, S., Chung, K.N. Biochemistry (1997) [Pubmed]
  18. Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. Molleran Lee, S., Villanueva, J., Sumegi, J., Zhang, K., Kogawa, K., Davis, J., Filipovich, A.H. J. Med. Genet. (2004) [Pubmed]
  19. Purification and characterization of a cytolytic pore-forming protein from granules of cloned lymphocytes with natural killer activity. Young, J.D., Hengartner, H., Podack, E.R., Cohn, Z.A. Cell (1986) [Pubmed]
  20. Localization and molecular modelling of the membrane-inserted domain of the ninth component of human complement and perforin. Peitsch, M.C., Amiguet, P., Guy, R., Brunner, J., Maizel, J.V., Tschopp, J. Mol. Immunol. (1990) [Pubmed]
  21. The pore-forming protein (perforin) of cytolytic T lymphocytes is immunologically related to the components of membrane attack complex of complement through cysteine-rich domains. Young, J.D., Liu, C.C., Leong, L.G., Cohn, Z.A. J. Exp. Med. (1986) [Pubmed]
  22. Importance of the P4' residue in human granzyme B inhibitors and substrates revealed by scanning mutagenesis of the proteinase inhibitor 9 reactive center loop. Sun, J., Whisstock, J.C., Harriott, P., Walker, B., Novak, A., Thompson, P.E., Smith, A.I., Bird, P.I. J. Biol. Chem. (2001) [Pubmed]
  23. Serine proteinase inhibitor-9, an endogenous blocker of granzyme B/perforin lytic pathway, is hyperexpressed during acute rejection of renal allografts. Muthukumar, T., Ding, R., Dadhania, D., Medeiros, M., Li, B., Sharma, V.K., Hartono, C., Serur, D., Seshan, S.V., Volk, H.D., Reinke, P., Kapur, S., Suthanthiran, M. Transplantation (2003) [Pubmed]
  24. Expression of recombinant human Met-ase-1: a NK cell-specific granzyme. Smyth, M.J., O'Connor, M.D., Kelly, J.M., Ganesvaran, P., Thia, K.Y., Trapani, J.A. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  25. Human CD59 is a receptor for the cholesterol-dependent cytolysin intermedilysin. Giddings, K.S., Zhao, J., Sims, P.J., Tweten, R.K. Nat. Struct. Mol. Biol. (2004) [Pubmed]
  26. Dipeptidyl peptidase I: importance of progranzyme activation sequences, other dipeptide sequences, and the N-terminal amino group of synthetic substrates for enzyme activity. Tran, T.V., Ellis, K.A., Kam, C.M., Hudig, D., Powers, J.C. Arch. Biochem. Biophys. (2002) [Pubmed]
  27. Group B streptococcal beta-hemolysin/cytolysin promotes invasion of human lung epithelial cells and the release of interleukin-8. Doran, K.S., Chang, J.C., Benoit, V.M., Eckmann, L., Nizet, V. J. Infect. Dis. (2002) [Pubmed]
  28. Effects of a complex mixture of therapeutic drugs at environmental levels on human embryonic cells. Pomati, F., Castiglioni, S., Zuccato, E., Fanelli, R., Vigetti, D., Rossetti, C., Calamari, D. Environ. Sci. Technol. (2006) [Pubmed]
  29. The ninth component of complement and the pore-forming protein (perforin 1) from cytotoxic T cells: structural, immunological, and functional similarities. Young, J.D., Cohn, Z.A., Podack, E.R. Science (1986) [Pubmed]
  30. Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis. Santoro, A., Cannella, S., Bossi, G., Gallo, F., Trizzino, A., Pende, D., Dieli, F., Bruno, G., Stinchcombe, J.C., Micalizzi, C., De Fusco, C., Danesino, C., Moretta, L., Notarangelo, L.D., Griffiths, G.M., Aric??, M. J. Med. Genet. (2006) [Pubmed]
  31. Review of hemophagocytic lymphohistiocytosis (HLH) in children with focus on Japanese experiences. Ishii, E., Ohga, S., Imashuku, S., Kimura, N., Ueda, I., Morimoto, A., Yamamoto, K., Yasukawa, M. Crit. Rev. Oncol. Hematol. (2005) [Pubmed]
  32. Novel SLA class I alleles of Chinese pig strains and their significance in xenotransplantation. Chen, F.X., Tang, J., Li, N.L., Shen, B.H., Zhou, Y., Xie, J., Chou, K.Y. Cell Res. (2003) [Pubmed]
  33. Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan. Ueda, I., Morimoto, A., Inaba, T., Yagi, T., Hibi, S., Sugimoto, T., Sako, M., Yanai, F., Fukushima, T., Nakayama, M., Ishii, E., Imashuku, S. Br. J. Haematol. (2003) [Pubmed]
  34. Structure of the mouse pore-forming protein (perforin) gene: analysis of transcription initiation site, 5' flanking sequence, and alternative splicing of 5' untranslated regions. Youn, B.S., Liu, C.C., Kim, K.K., Young, J.D., Kwon, M.H., Kwon, B.S. J. Exp. Med. (1991) [Pubmed]
  35. Constitutive expression of pore-forming protein in peripheral blood gamma/delta T cells: implication for their cytotoxic role in vivo. Nakata, M., Smyth, M.J., Norihisa, Y., Kawasaki, A., Shinkai, Y., Okumura, K., Yagita, H. J. Exp. Med. (1990) [Pubmed]
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