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Gene Review

PCNA  -  proliferating cell nuclear antigen

Homo sapiens

Synonyms: Cyclin, Proliferating cell nuclear antigen
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Disease relevance of PCNA


Psychiatry related information on PCNA

  • In OLP, no significant correlations were found between p53 or PCNA expression and the patients' age, gender, lesion duration, location, size, number of site, presence of pain, presence of local irritant, and the habits of alcohol drinking and cigarette smoking (all P > .05) [6].
  • Furthermore, smoking cessation during therapy correlated well with reduced PCNA expression (P = 0.006), although multivariate analysis indicated that this reduction in PCNA expression was associated with the reversal of squamous metaplasia [7].
  • These results suggest that the PCNA index can be used in decision making for treatment and assessment of prognosis in laryngeal carcinomas [8].
  • In the present study we have demonstrated the presence of cannabinoid CB1 receptors, which are preferentially lost in Huntington's disease, colocalised with the proliferative marker PCNA in the adult normal and Huntington's disease subependymal layer [9].
  • We have used immunohistochemical techniques and a monoclonal antibody against proliferating cell nuclear antigen (PCNA) to investigate the proliferative activity of glial cells in mice with experimental Creutzfeldt-Jakob disease (CJD), and in human cases of CJD, kuru and Gerstmann-Sträussler-Scheinker syndrome (GSS) [10].

High impact information on PCNA

  • Ablation of Evi5 induces precocious degradation of Emi1 by the Plk/SCF(betaTrCP) pathway, causing premature APC/C activation; cyclin destruction; cell-cycle arrest; centrosome overduplication; and, finally, mitotic catastrophe [11].
  • The evi5 oncogene regulates cyclin accumulation by stabilizing the anaphase-promoting complex inhibitor emi1 [11].
  • The retinoblastoma (Rb) protein negatively regulates the G1-S transition by binding to the E2F transcription factors, until cyclin-dependent kinases phosphorylate Rb, causing E2F release [12].
  • In this issue of Cell, Mailand and Diffley (2005) show that phosphorylation of Cdc6 by cyclin-dependent kinases prevents its destruction by the anaphase promoting complex (APC) [13].
  • I discuss advances in the cell cycle in the 21 years since cyclin was discovered [14].

Chemical compound and disease context of PCNA


Biological context of PCNA


Anatomical context of PCNA


Associations of PCNA with chemical compounds


Physical interactions of PCNA


Enzymatic interactions of PCNA


Co-localisations of PCNA


Regulatory relationships of PCNA

  • Proliferating cell nuclear antigen (PCNA) was able to stimulate both acetylated and unacetylated Fen1 activity to the same extent [47].
  • Consistent with previous reports, expression of cyclin D1a inhibited cell-cycle progression in AR-dependent prostate cancer cells [48].
  • Tetrandrine induces early G1 arrest in human colon carcinoma cells by down-regulating the activity and inducing the degradation of G1-S-specific cyclin-dependent kinases and by inducing p53 and p21Cip1 [49].
  • A model was proposed in which, during p53-mediated suppression of cell proliferation following treatment with 254 nm UV radiation (UVC), the enhanced expression of p21 might inhibit DNA replication by virtue of its interactions with proliferating cell nuclear antigen [50].
  • The cyclin-activated cdc2 family kinases may target their cellular substrates through cyclin-mediated protein-protein interactions [51].
  • Knockdown of MTH2 significantly promoted degradation of PCNA, suggesting that the physiological interaction of PCNA-MTH2 may confer protection from degradation for PCNA, whereas UV irradiation accelerates PCNA degradation by inducing dissociation of PCNA-MTH2 [52].

Other interactions of PCNA

  • An intact trimeric ring is maintained in the structure of the p21-PCNA complex, with a central hole available for DNA interaction [33].
  • The PCNA-binding domain is sufficient for inhibition of DNA replication based on simian virus 40, whereas the Cdk2-binding domain is sufficient for inhibition of DNA replication based on Xenopus egg extract and for growth suppression in transformed human cells [53].
  • Finally, we show that in addition to threonine 187 phosphorylation, efficient p27 ubiquitination requires formation of a trimeric complex with the cyclin and Cdk subunits [54].
  • Cyclin E is classified as a putative G1 cyclin on the basis of its cyclic pattern of mRNA expression, with maximal levels being detected near the G1/S boundary [55].
  • Structural basis for recruitment of human flap endonuclease 1 to PCNA [36].

Analytical, diagnostic and therapeutic context of PCNA


  1. Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair. Li, R., Waga, S., Hannon, G.J., Beach, D., Stillman, B. Nature (1994) [Pubmed]
  2. Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein. Funk, J.O., Waga, S., Harry, J.B., Espling, E., Stillman, B., Galloway, D.A. Genes Dev. (1997) [Pubmed]
  3. Rofecoxib inhibits cyclooxygenase 2 expression and activity and reduces cell proliferation in Barrett's esophagus. Kaur, B.S., Khamnehei, N., Iravani, M., Namburu, S.S., Lin, O., Triadafilopoulos, G. Gastroenterology (2002) [Pubmed]
  4. Transcriptional activation of the human proliferating-cell nuclear antigen promoter by p53. Morris, G.F., Bischoff, J.R., Mathews, M.B. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  5. Relationship of p53 overexpression and up-regulation of proliferating cell nuclear antigen with the clinical course of non-small cell lung cancer. Ebina, M., Steinberg, S.M., Mulshine, J.L., Linnoila, R.I. Cancer Res. (1994) [Pubmed]
  6. Higher expressions of p53 and proliferating cell nuclear antigen (PCNA) in atrophic oral lichen planus and patients with areca quid chewing. Lee, J.J., Kuo, M.Y., Cheng, S.J., Chiang, C.P., Jeng, J.H., Chang, H.H., Kuo, Y.S., Lan, W.H., Kok, S.H. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. (2005) [Pubmed]
  7. Modulation of proliferating cell nuclear antigen in the bronchial epithelium of smokers. Khuri, F.R., Lee, J.S., Lippman, S.M., Lee, J.J., Kalapurakal, S., Yu, R., Ro, J.Y., Morice, R.C., Hong, W.K., Hittelman, W.N. Cancer Epidemiol. Biomarkers Prev. (2001) [Pubmed]
  8. Prognostic significance of PCNA expression in laryngeal cancer. Saraç, S., Ayhan, A., Hosal, A.S., Kaya, S. Arch. Otolaryngol. Head Neck Surg. (1998) [Pubmed]
  9. A novel population of progenitor cells expressing cannabinoid receptors in the subependymal layer of the adult normal and Huntington's disease human brain. Curtis, M.A., Faull, R.L., Glass, M. J. Chem. Neuroanat. (2006) [Pubmed]
  10. Proliferating cell nuclear antigen immunohistochemistry in astrocytes in experimental Creutzfeldt-Jakob disease and in human kuru, Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker syndrome. Biernat, W., Liberski, P.P., Guiroy, D.C., Yanagihara, R., Gajdusek, D.C. Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration. (1995) [Pubmed]
  11. The evi5 oncogene regulates cyclin accumulation by stabilizing the anaphase-promoting complex inhibitor emi1. Eldridge, A.G., Loktev, A.V., Hansen, D.V., Verschuren, E.W., Reimann, J.D., Jackson, P.K. Cell (2006) [Pubmed]
  12. Structure of the Rb C-terminal domain bound to E2F1-DP1: a mechanism for phosphorylation-induced E2F release. Rubin, S.M., Gall, A.L., Zheng, N., Pavletich, N.P. Cell (2005) [Pubmed]
  13. CDKs give Cdc6 a license to drive into S phase. Ayad, N.G. Cell (2005) [Pubmed]
  14. Recycling the cell cycle: cyclins revisited. Murray, A.W. Cell (2004) [Pubmed]
  15. Progesterone receptor modulator CDB-2914 down-regulates proliferative cell nuclear antigen and Bcl-2 protein expression and up-regulates caspase-3 and poly(adenosine 5'-diphosphate-ribose) polymerase expression in cultured human uterine leiomyoma cells. Xu, Q., Takekida, S., Ohara, N., Chen, W., Sitruk-Ware, R., Johansson, E.D., Maruo, T. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  16. A novel selective progesterone receptor modulator asoprisnil (J867) inhibits proliferation and induces apoptosis in cultured human uterine leiomyoma cells in the absence of comparable effects on myometrial cells. Chen, W., Ohara, N., Wang, J., Xu, Q., Liu, J., Morikawa, A., Sasaki, H., Yoshida, S., Demanno, D.A., Chwalisz, K., Maruo, T. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  17. Growth fraction in centrocytic and follicular center cell lymphomas: assessment in paraffin sections with a proliferating cell nuclear antigen antibody and morphometric correlates. Swerdlow, S.H., Westermann, C.D., Pelstring, R.J., Saboorian, M.H., Williams, M.E. Hum. Pathol. (1993) [Pubmed]
  18. Effects of daily low dose mifepristone on endometrial maturation and proliferation. Cameron, S.T., Critchley, H.O., Thong, K.J., Buckley, C.H., Williams, A.R., Baird, D.T. Hum. Reprod. (1996) [Pubmed]
  19. Differential sensitivity of human mammary epithelial and breast carcinoma cell lines to curcumin. Ramachandran, C., You, W. Breast Cancer Res. Treat. (1999) [Pubmed]
  20. D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Xiong, Y., Zhang, H., Beach, D. Cell (1992) [Pubmed]
  21. Replication-dependent marking of DNA by PCNA facilitates CAF-1-coupled inheritance of chromatin. Shibahara, K., Stillman, B. Cell (1999) [Pubmed]
  22. Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. Xiong, Y., Zhang, H., Beach, D. Genes Dev. (1993) [Pubmed]
  23. Cyclin D1-mediated inhibition of repair and replicative DNA synthesis in human fibroblasts. Pagano, M., Theodoras, A.M., Tam, S.W., Draetta, G.F. Genes Dev. (1994) [Pubmed]
  24. The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2. Opresko, P.L., Otterlei, M., Graakjaer, J., Bruheim, P., Dawut, L., Kølvraa, S., May, A., Seidman, M.M., Bohr, V.A. Mol. Cell (2004) [Pubmed]
  25. Proliferating cell nuclear antigen promotes DNA synthesis past template lesions by mammalian DNA polymerase delta. Mozzherin, D.J., Shibutani, S., Tan, C.K., Downey, K.M., Fisher, P.A. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  26. Distribution of hyaluronan during extracellular matrix remodeling in human restenotic arteries and balloon-injured rat carotid arteries. Riessen, R., Wight, T.N., Pastore, C., Henley, C., Isner, J.M. Circulation (1996) [Pubmed]
  27. Increased cell proliferation and neurogenesis in the adult human Huntington's disease brain. Curtis, M.A., Penney, E.B., Pearson, A.G., van Roon-Mom, W.M., Butterworth, N.J., Dragunow, M., Connor, B., Faull, R.L. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  28. DNA ligase I is recruited to sites of DNA replication by an interaction with proliferating cell nuclear antigen: identification of a common targeting mechanism for the assembly of replication factories. Montecucco, A., Rossi, R., Levin, D.S., Gary, R., Park, M.S., Motycka, T.A., Ciarrocchi, G., Villa, A., Biamonti, G., Tomkinson, A.E. EMBO J. (1998) [Pubmed]
  29. Histopathology of in-stent restenosis in patients with peripheral artery disease. Kearney, M., Pieczek, A., Haley, L., Losordo, D.W., Andres, V., Schainfeld, R., Rosenfield, K., Isner, J.M. Circulation (1997) [Pubmed]
  30. Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways. Hussain, S., Wilson, J.B., Medhurst, A.L., Hejna, J., Witt, E., Ananth, S., Davies, A., Masson, J.Y., Moses, R., West, S.C., de Winter, J.P., Ashworth, A., Jones, N.J., Mathew, C.G. Hum. Mol. Genet. (2004) [Pubmed]
  31. Cyclin-dependent kinase inhibitor p21 modulates the DNA primer-template recognition complex. Waga, S., Stillman, B. Mol. Cell. Biol. (1998) [Pubmed]
  32. Neoadjuvant percutaneous 4-hydroxytamoxifen decreases breast tumoral cell proliferation: a prospective controlled randomized study comparing three doses of 4-hydroxytamoxifen gel to oral tamoxifen. Rouanet, P., Linares-Cruz, G., Dravet, F., Poujol, S., Gourgou, S., Simony-Lafontaine, J., Grenier, J., Kramar, A., Girault, J., Le Nestour, E., Maudelonde, T. J. Clin. Oncol. (2005) [Pubmed]
  33. Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA. Gulbis, J.M., Kelman, Z., Hurwitz, J., O'Donnell, M., Kuriyan, J. Cell (1996) [Pubmed]
  34. Prolonged induction of p21Cip1/WAF1/CDK2/PCNA complex by epidermal growth factor receptor activation mediates ligand-induced A431 cell growth inhibition. Fan, Z., Lu, Y., Wu, X., DeBlasio, A., Koff, A., Mendelsohn, J. J. Cell Biol. (1995) [Pubmed]
  35. Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. Parry, D., Bates, S., Mann, D.J., Peters, G. EMBO J. (1995) [Pubmed]
  36. Structural basis for recruitment of human flap endonuclease 1 to PCNA. Sakurai, S., Kitano, K., Yamaguchi, H., Hamada, K., Okada, K., Fukuda, K., Uchida, M., Ohtsuka, E., Morioka, H., Hakoshima, T. EMBO J. (2005) [Pubmed]
  37. P21Cip1/WAF1 downregulation is required for efficient PCNA ubiquitination after UV irradiation. Soria, G., Podhajcer, O., Prives, C., Gottifredi, V. Oncogene (2006) [Pubmed]
  38. Cyclin-dependent kinases phosphorylate human Cdt1 and induce its degradation. Liu, E., Li, X., Yan, F., Zhao, Q., Wu, X. J. Biol. Chem. (2004) [Pubmed]
  39. Perturbation of the p53 response by human papillomavirus type 16 E7. Hickman, E.S., Bates, S., Vousden, K.H. J. Virol. (1997) [Pubmed]
  40. Terminal deoxynucleotidyltransferase is negatively regulated by direct interaction with proliferating cell nuclear antigen. Ibe, S., Fujita, K., Toyomoto, T., Shimazaki, N., Kaneko, R., Tanabe, A., Takebe, I., Kuroda, S., Kobayashi, T., Toji, S., Tamai, K., Yamamoto, H., Koiwai, O. Genes Cells (2001) [Pubmed]
  41. Cdk-interacting protein 1 directly binds with proliferating cell nuclear antigen and inhibits DNA replication catalyzed by the DNA polymerase delta holoenzyme. Flores-Rozas, H., Kelman, Z., Dean, F.B., Pan, Z.Q., Harper, J.W., Elledge, S.J., O'Donnell, M., Hurwitz, J. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  42. In human hepatocellular carcinoma in cirrhosis proliferating cell nuclear antigen (PCNA) is involved in cell proliferation and cooperates with P21 in DNA repair. Gramantieri, L., Trerè, D., Chieco, P., Lacchini, M., Giovannini, C., Piscaglia, F., Cavallari, A., Bolondi, L. J. Hepatol. (2003) [Pubmed]
  43. XRCC1 co-localizes and physically interacts with PCNA. Fan, J., Otterlei, M., Wong, H.K., Tomkinson, A.E., Wilson, D.M. Nucleic Acids Res. (2004) [Pubmed]
  44. Gene expression of flap endonuclease-1 during cell proliferation and differentiation. Kim, I.S., Lee, M.Y., Lee, I.H., Shin, S.L., Lee, S.Y. Biochim. Biophys. Acta (2000) [Pubmed]
  45. DNA damage-induced accumulation of Rad18 protein at stalled replication forks in mammalian cells involves upstream protein phosphorylation. Nikiforov, A., Svetlova, M., Solovjeva, L., Sasina, L., Siino, J., Nazarov, I., Bradbury, M., Tomilin, N. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  46. Human DNA polymerase epsilon colocalizes with proliferating cell nuclear antigen and DNA replication late, but not early, in S phase. Fuss, J., Linn, S. J. Biol. Chem. (2002) [Pubmed]
  47. Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300. Hasan, S., Stucki, M., Hassa, P.O., Imhof, R., Gehrig, P., Hunziker, P., Hübscher, U., Hottiger, M.O. Mol. Cell (2001) [Pubmed]
  48. Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation. Burd, C.J., Petre, C.E., Morey, L.M., Wang, Y., Revelo, M.P., Haiman, C.A., Lu, S., Fenoglio-Preiser, C.M., Li, J., Knudsen, E.S., Wong, J., Knudsen, K.E. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  49. Tetrandrine induces early G1 arrest in human colon carcinoma cells by down-regulating the activity and inducing the degradation of G1-S-specific cyclin-dependent kinases and by inducing p53 and p21Cip1. Meng, L.H., Zhang, H., Hayward, L., Takemura, H., Shao, R.G., Pommier, Y. Cancer Res. (2004) [Pubmed]
  50. p53-dependent signaling sustains DNA replication and enhances clonogenic survival in 254 nm ultraviolet-irradiated human fibroblasts. Cistulli, C.A., Kaufmann, W.K. Cancer Res. (1998) [Pubmed]
  51. Characterization of the in vitro reconstituted cyclin A or B1-dependent cdk2 and cdc2 kinase activities. Pan, Z.Q., Amin, A., Hurwitz, J. J. Biol. Chem. (1993) [Pubmed]
  52. Proliferating cell nuclear antigen is protected from degradation by forming a complex with MutT Homolog2. Yu, Y., Cai, J.P., Tu, B., Wu, L., Zhao, Y., Liu, X., Li, L., McNutt, M.A., Feng, J., He, Q., Yang, Y., Wang, H., Sekiguchi, M., Zhu, W.G. J. Biol. Chem. (2009) [Pubmed]
  53. Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA. Chen, J., Jackson, P.K., Kirschner, M.W., Dutta, A. Nature (1995) [Pubmed]
  54. Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation. Montagnoli, A., Fiore, F., Eytan, E., Carrano, A.C., Draetta, G.F., Hershko, A., Pagano, M. Genes Dev. (1999) [Pubmed]
  55. Cyclin E/cdk2 and cyclin A/cdk2 kinases associate with p107 and E2F in a temporally distinct manner. Lees, E., Faha, B., Dulic, V., Reed, S.I., Harlow, E. Genes Dev. (1992) [Pubmed]
  56. Studies on the interactions between human replication factor C and human proliferating cell nuclear antigen. Zhang, G., Gibbs, E., Kelman, Z., O'Donnell, M., Hurwitz, J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  57. Temporally and spatially coordinated expression of cell cycle regulatory factors after angioplasty. Wei, G.L., Krasinski, K., Kearney, M., Isner, J.M., Walsh, K., Andrés, V. Circ. Res. (1997) [Pubmed]
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