Tumor Biology

, Volume 37, Issue 9, pp 12697–12711 | Cite as

The alpha-fetoprotein (AFP) third domain: a search for AFP interaction sites of cell cycle proteins

  • G. J. Mizejewski
Original Article


The carboxy-terminal third domain of alpha-fetoprotein (AFP-3D) is known to harbor binding and/or interaction sites for hydrophobic ligands, receptors, and binding proteins. Such reports have established that AFP-3D consists of amino acid (AA) sequence stretches on the AFP polypeptide that engages in protein-to-protein interactions with various ligands and receptors. Using a computer software program specifically designed for such interactions, the present report identified AA sequence fragments on AFP-3D that could potentially interact with a variety of cell cycle proteins. The cell cycle proteins identified were (1) cyclins, (2) cyclin-dependent kinases, (3) cell cycle-associated proteins (inhibitors, checkpoints, initiators), and (4) ubiquitin ligases. Following detection of the AFP-3D to cell cycle protein interaction sites, the computer-derived AFP localization AA sequences were compared and aligned with previously reported hydrophobic ligand and receptor interaction sites on AFP-3D. A literature survey of the association of cell cycle proteins with AFP showed both positive relationships and correlations. Previous reports of experimental AFP-derived peptides effects on various cell cycle proteins served to confirm and verify the present computer cell cycle protein identifications. Cell cycle protein interactions with AFP-CD peptides have been reported in cultured MCF-7 breast cancer cells subjected to mRNA microarray analysis. After 7 days in culture with MCF-7 cells, the AFP-derived peptides were shown to downregulate cyclin E, SKP2, checkpoint suppressors, cyclin-dependent kinases, and ubiquitin ligases that modulate cyclin E/CdK2 transition from the G1 to the S-phase of the cell cycle. Thus, the experimental data on AFP-CD interaction with cell cycle proteins were consistent with the “in silico” findings.


Cyclins Alpha-fetoprotein Cell cycle Third domain Ubiquitin Cyclin-dependent kinases 


Compliance with ethical standards

Conflicts of interest



  1. 1.
    Mizejewski GJ. Alpha-fetoprotein structure and function: relevance to isoforms, epitopes, and conformational variants. Exp Biol Med (Maywood). 2001;226:377–408.Google Scholar
  2. 2.
    Naidu S, Peterson ML, Spear BT. Alpha-fetoprotein related gene (ARG): a new member of the albumin gene family that is no longer functional in primates. Gene. 2010;449:95–102.PubMedCrossRefGoogle Scholar
  3. 3.
    Mizejewski GJ. Alpha-fetoprotein as a biologic response modifier: relevance to domain and subdomain structure. Proc Soc Exp Biol Med. 1997;215:333–62.PubMedCrossRefGoogle Scholar
  4. 4.
    Mizejewski GJ. Biological role of alpha-fetoprotein in cancer: prospects for anticancer therapy. Expert Rev Anticancer Ther. 2002;2:709–35.PubMedCrossRefGoogle Scholar
  5. 5.
    Luft AJ, Lorscheider FL. Structural analysis of human and bovine alpha-fetoprotein by electron microscopy, image processing, and circular dichroism. Biochemistry. 1983;22:5978–81.PubMedCrossRefGoogle Scholar
  6. 6.
    Strop P, Zizkovsky V, Korcakova J, Havranova M, Mikes F. Conformational transitions of human alpha-1 fetoprotein and serum albumin at acid and alkaline pH. Int J Biochem. 1984;16:805–13.PubMedCrossRefGoogle Scholar
  7. 7.
    Laderoute M, Willans D, Wegmann T, Longenecker M. The identification, isolation and characterization of a 67 kilodalton, PNA-reactive autoantigen commonly expressed in human adenocarcinomas. Anticancer Res. 1994;14:1233–45.PubMedGoogle Scholar
  8. 8.
    Suzuki Y, Zeng CQ, Alpert E. Isolation and partial characterization of a specific alpha-fetoprotein receptor on human monocytes. J Clin Invest. 1992;90:1530–6.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Moro R, Tamaoki T, Wegmann TG, Longenecker BM, Laderoute MP. Monoclonal antibodies directed against a widespread oncofetal antigen: the alpha-fetoprotein receptor. Tumour Biol. 1993;14:116–30.PubMedCrossRefGoogle Scholar
  10. 10.
    Torres JM, Darracq N, Uriel J. Membrane proteins from lymphoblastoid cells showing cross-affinity for alpha-fetoprotein and albumin. Isolation Charact Biochim Biophys Acta. 1992;1159:60–6.CrossRefGoogle Scholar
  11. 11.
    Atemezem A, Mbemba E, Marfaing R, Vaysse J, Pontet M, Saffar L, Charnaux N, Gattegno L. Human alpha-fetoprotein binds to primary macrophages. Biochem Biophys Res Commun. 2002;296:507–14.PubMedCrossRefGoogle Scholar
  12. 12.
    Mizejewski GJ. Review of the putative cell-surface receptors for alpha-fetoprotein: identification of a candidate receptor protein family. Tumour Biol. 2011;32:241–58.PubMedCrossRefGoogle Scholar
  13. 13.
    Mizejewski GJ. The adenocarcinoma cell surface mucin receptor for alpha-fetoprotein: is the same receptor present on circulating monocytes and macrophages? A commentary. Tumour Biol. 2014;35:7397–402.PubMedCrossRefGoogle Scholar
  14. 14.
    Mizejewski GJ. Nonsecreted cytoplasmic alpha-fetoprotein: a newly discovered role in intracellular signaling and regulation. An update and commentary. Tumor Biol. 2015:1–8.Google Scholar
  15. 15.
    Posypanova GA, Gorokhovets NV, Makarov VA, Savvateeva LV, Kireeva NN, Severin SE, Severin ES. Recombinant alpha-fetoprotein C-terminal fragment: the new recombinant vector for targeted delivery. J Drug Target. 2008;16:321–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Godovannyi AV, Vorontsov EA, Gukasova NV, Pozdnyakova NV, Vasilenko EA, Yabbarov NG, Dubovik EG, Severin SE, Severin ES, Gnuchev NV. Targeted delivery of paclitaxel-loaded recombinant alpha-fetoprotein fragment-conjugated nanoparticles to tumor cells. Dokl Biochem Biophys. 2011;439:158–60.PubMedCrossRefGoogle Scholar
  17. 17.
    Posypanova GA, Makarov VA, Savvateeva MV, Bereznikova AV, Severin ES. The receptor binding fragment of alpha-fetoprotein is a promising new vector for the selective delivery of antineoplastic agents. J Drug Target. 2013;21:458–65.PubMedCrossRefGoogle Scholar
  18. 18.
    Yabbarov NG, Posypanova GA, Vorontsov EA, Obydenny SI, Severin ES. A new system for targeted delivery of doxorubicin into tumor cells. J Control Release. 2013;168:135–41.PubMedCrossRefGoogle Scholar
  19. 19.
    Mizejewski GJ, Mirowski M, Garnuszek P, Maurin M, Cohen BD, Poiesz BJ, Posypanova GA, Makarov VA, Severin ES, Severin SE. Targeted delivery of anti-cancer growth inhibitory peptides derived from human alpha-fetoprotein: review of an international multi-center collaborative study. J Drug Target. 2010;18:575–88.PubMedCrossRefGoogle Scholar
  20. 20.
    Mizejewski GJ. The alpha-fetoprotein third domain receptor binding fragment: in search of scavenger and associated receptor targets. J Drug Target. 2015:1–14.Google Scholar
  21. 21.
    Aussel C, Masseyeff R. Interaction of retinoids and bilirubin with the binding of arachidonic acid to human alpha-fetoprotein. Biochem Biophys Res Commun. 1984;119:1122–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Benassayag C, Savu L, Vallette G, Delorme J, Nunez EA. Relations between fatty acids and oestrogen binding properties of pure rat alpha 1-foetoprotein. Biochim Biophys Acta. 1979;587:227–37.PubMedCrossRefGoogle Scholar
  23. 23.
    Li C, Wang S, Jiang W, Li H, Liu Z, Zhang C, McNutt MA, Li G. Impact of intracellular alpha fetoprotein on retinoic acid receptors-mediated expression of GADD153 in human hepatoma cell lines. Int J Cancer. 2012;130:754–64.PubMedCrossRefGoogle Scholar
  24. 24.
    Mizejewski GJ. Review of the adenocarcinoma cell surface receptor for human alpha-fetoprotein; proposed identification of a widespread mucin as the tumor cell receptor. Tumour Biol. 2013;34:1317–36.PubMedCrossRefGoogle Scholar
  25. 25.
    Pardee AD, Hiroshi Y, Aaron P, Normolle DP, Vujanovic L, Mizejewski GJ, Watkins SC, Butterfield LH. Route of antigen delivery dictates the immunostimulatory activity of dendritic cell-based vaccines for hepatocellular carcinoma. J Immunother Cancer. 2015; In press.Google Scholar
  26. 26.
    Cooper GM. Chapter 14: the eukaryotic cell cycle; the cell: a molecular approach. Washington, DC: ASM Press; 2000.Google Scholar
  27. 27.
    Morgan DO. The cell cycle: principles of control. London: New Science Press in association with Oxford University Press; 2007.Google Scholar
  28. 28.
    Nigg EA. Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle. BioEssays. 1995;17:471–80.PubMedCrossRefGoogle Scholar
  29. 29.
    Lilly MA, Duronio RJ. New insights into cell cycle control from the Drosophila endocycle. Oncogene. 2005;24:2765–75.PubMedCrossRefGoogle Scholar
  30. 30.
    Brown NR, Noble ME, Endicott JA, Johnson LN. The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases. Nat Cell Biol. 1999;1:438–43.PubMedCrossRefGoogle Scholar
  31. 31.
    Orlando DA, Lin CY, Bernard A, Wang JY, Socolar JE, Iversen ES, Hartemink AJ, Haase SB. Global control of cell-cycle transcription by coupled CDK and network oscillators. Nature. 2008;453:944–7.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Lazareva MN. Alpha-fetoprotein production by the synchronized regenerating murine liver. Its independence on the phases of the mitotic cycle. Oncodev Biol Med. 1981;2:89–99.PubMedGoogle Scholar
  33. 33.
    Mizejewski GJ. Mechanism of cancer growth suppression of alpha-fetoprotein derived growth inhibitory peptides (GIP): comparison of GIP-34 versus GIP-8 (AFPep). Updates and prospects. Cancers (Basel). 2011;3:2709–33.CrossRefGoogle Scholar
  34. 34.
    Carter DC, He XM, Munson SH, Twigg PD, Gernert KM, Broom MB, Miller TY. Three-dimensional structure of human serum albumin. Science. 1989;244:1195–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Osmond RI, Das S, Crouch MF. Development of cell-based assays for cytokine receptor signaling, using an AlphaScreen SureFire assay format. Anal Biochem. 2010;403:94–101.PubMedCrossRefGoogle Scholar
  36. 36.
    Galderisi U, Jori FP, Giordano A. Cell cycle regulation and neural differentiation. Oncogene. 2003;22:5208–19.PubMedCrossRefGoogle Scholar
  37. 37.
    Rahman MM, Kipreos ET. The specific roles of mitotic cyclins revealed. Cell Cycle. 2010;9:22–3.PubMedCrossRefGoogle Scholar
  38. 38.
    Fung TK, Poon RY. A roller coaster ride with the mitotic cyclins. Semin Cell Dev Biol. 2005;16:335–42.PubMedCrossRefGoogle Scholar
  39. 39.
    Monty Krieger MPS, Matsudaira PT, Lodish HF, Darnell JE, LZipursky L, Kaiser C, Berk A. Molecular cell biology. Fifth ed. New York: W.H. Freeman and Co.; 2004.Google Scholar
  40. 40.
    Yang J, Song H, Walsh S, Bardes ES, Kornbluth S. Combinatorial control of cyclin B1 nuclear trafficking through phosphorylation at multiple sites. J Biol Chem. 2001;276:3604–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Brown NR, Noble ME, Endicott JA, Garman EF, Wakatsuki S, Mitchell E, Rasmussen B, Hunt T, Johnson LN. The crystal structure of cyclin A. Structure. 1995;3:1235–47.PubMedCrossRefGoogle Scholar
  42. 42.
    Davies TG, Tunnah P, Meijer L, Marko D, Eisenbrand G, Endicott JA, Noble ME. Inhibitor binding to active and inactive CDK2: the crystal structure of CDK2-cyclin A/indirubin-5-sulphonate. Structure. 2001;9:389–97.PubMedCrossRefGoogle Scholar
  43. 43.
    Yang R, Nakamaki T, Lubbert M, Said J, Sakashita A, Freyaldenhoven BS, Spira S, Huynh V, Muller C, Koeffler HP. Cyclin A1 expression in leukemia and normal hematopoietic cells. Blood. 1999;93:2067–74.PubMedGoogle Scholar
  44. 44.
    Ravnik SE, Wolgemuth DJ. Regulation of meiosis during mammalian spermatogenesis: the A-type cyclins and their associated cyclin-dependent kinases are differentially expressed in the germ-cell lineage. Dev Biol. 1999;207:408–18.PubMedCrossRefGoogle Scholar
  45. 45.
    Pines J, Hunter T. Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2. Cell. 1989;58:833–46.PubMedCrossRefGoogle Scholar
  46. 46.
    Innocente SA, Abrahamson JL, Cogswell JP, Lee JM. p53 regulates a G2 checkpoint through cyclin B1. Proc Natl Acad Sci U S A. 1999;96:2147–52.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Kawamoto H, Koizumi H, Uchikoshi T. Expression of the G2-M checkpoint regulators cyclin B1 and cdc2 in nonmalignant and malignant human breast lesions: immunocytochemical and quantitative image analyses. Am J Pathol. 1997;150:15–23.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Wang A, Yoshimi N, Ino N, Tanaka T, Mori H. Overexpression of cyclin B1 in human colorectal cancers. J Cancer Res Clin Oncol. 1997;123:124–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Mashal RD, Lester S, Corless C, Richie JP, Chandra R, Propert KJ, Dutta A. Expression of cell cycle-regulated proteins in prostate cancer. Cancer Res. 1996;56:4159–63.PubMedGoogle Scholar
  50. 50.
    Inaba T, Matsushime H, Valentine M, Roussel MF, Sherr CJ, Look AT. Genomic organization, chromosomal localization, and independent expression of human cyclin D genes. Genomics. 1992;13:565–74.PubMedCrossRefGoogle Scholar
  51. 51.
    Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 1993;7:812–21.PubMedCrossRefGoogle Scholar
  52. 52.
    Nakajima K, Crisma AR, Silva GB, Rogero MM, Fock RA, Borelli P. Malnutrition suppresses cell cycle progression of hematopoietic progenitor cells in mice via cyclin D1 down-regulation. Nutrition. 2014;30:82–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Jares P, Colomer D, Campo E. Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nat Rev Cancer. 2007;7:750–62.PubMedCrossRefGoogle Scholar
  54. 54.
    Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides RJ. CDK-independent activation of estrogen receptor by cyclin D1. Cell. 1997;88:405–15.PubMedCrossRefGoogle Scholar
  55. 55.
    Morris L, Allen KE, La Thangue NB. Regulation of E2F transcription by cyclin E-Cdk2 kinase mediated through p300/CBP co-activators. Nat Cell Biol. 2000;2:232–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv Cancer Res. 1996;68:67–108.PubMedCrossRefGoogle Scholar
  57. 57.
    Chen Z, Indjeian VB, McManus M, Wang L, Dynlacht BD. CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells. Dev Cell. 2002;3:339–50.PubMedCrossRefGoogle Scholar
  58. 58.
    Cooley A, Zelivianski S, Jeruss JS. Impact of cyclin E overexpression on Smad3 activity in breast cancer cell lines. Cell Cycle. 2010;9:4900–7.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Kitahara K, Yasui W, Kuniyasu H, Yokozaki H, Akama Y, Yunotani S, Hisatsugu T, Tahara E. Concurrent amplification of cyclin E and CDK2 genes in colorectal carcinomas. Int J Cancer. 1995;62:25–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Huang LN, Wang DS, Chen YQ, Li W, Hu FD, Gong BL, Zhao CL, Jia W. Meta-analysis for cyclin E in lung cancer survival. Clin Chim Acta. 2012;413:663–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Tassan JP, Jaquenoud M, Fry AM, Frutiger S, Hughes GJ, Nigg EA. In vitro assembly of a functional human CDK7-cyclin H complex requires MAT1, a novel 36 kDa RING finger protein. EMBO J. 1995;14:5608–17.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Fisher RP, Morgan DO. A novel cyclin associates with MO15/CDK7 to form the CDK-activating kinase. Cell. 1994;78:713–24.PubMedCrossRefGoogle Scholar
  63. 63.
    Feaver WJ, Svejstrup JQ, Henry NL, Kornberg RD. Relationship of CDK-activating kinase and RNA polymerase II CTD kinase TFIIH/TFIIK. Cell. 1994;79:1103–9.PubMedCrossRefGoogle Scholar
  64. 64.
    De Bondt HL, Rosenblatt J, Jancarik J, Jones HD, Morgan DO, Kim SH. Crystal structure of cyclin-dependent kinase 2. Nature. 1993;363:595–602.PubMedCrossRefGoogle Scholar
  65. 65.
    Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massague J, Pavletich NP. Mechanism of CDK activation revealed by the structure of a cyclin A-CDK2 complex. Nature. 1995;376:313–20.PubMedCrossRefGoogle Scholar
  66. 66.
    Skotheim JM, Di Talia S, Siggia ED, Cross FR. Positive feedback of G1 cyclins ensures coherent cell cycle entry. Nature. 2008;454:291–6.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Tsai LH, Harlow E, Meyerson M. Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase. Nature. 1991;353:174–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan DO, Franza BR, Roberts JM. Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science. 1992;257:1689–94.PubMedCrossRefGoogle Scholar
  69. 69.
    Connor MK, Kotchetkov R, Cariou S, Resch A, Lupetti R, Beniston RG, Melchior F, Hengst L, Slingerland JM. CRM1/Ran-mediated nuclear export of p27(Kip1) involves a nuclear export signal and links p27 export and proteolysis. Mol Biol Cell. 2003;14:201–13.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev. 1993;7:331–42.PubMedCrossRefGoogle Scholar
  71. 71.
    Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM. Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells. Proc Natl Acad Sci U S A. 2000;97:9042–6.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Xiong Y, Zhang H, Beach D. Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. Genes Dev. 1993;7:1572–83.PubMedCrossRefGoogle Scholar
  73. 73.
    Meyerson M, Harlow E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol. 1994;14:2077–86.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Bertoli C, Skotheim JM, de Bruin RA. Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Cell Biol. 2013;14:518–28.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Lin J, Jinno S, Okayama H. Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell’s proliferation competence. Oncogene. 2001;20:2000–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Chen P, Luo C, Deng Y, Ryan K, Register J, Margosiak S, Tempczyk-Russell A, Nguyen B, Myers P, Lundgren K, Kan CC, O’Connor PM. The 1.7 A crystal structure of human cell cycle checkpoint kinase Chk1: implications for Chk1 regulation. Cell. 2000;100:681–92.PubMedCrossRefGoogle Scholar
  77. 77.
    Cai L, Struk B, Adams MD, Ji W, Haaf T, Kang HL, Dho SH, Xu X, Ringpfeil F, Nancarrow J, Zach S, Schaen L, Stumm M, Niu T, Chung J, Lunze K, Verrecchia B, Goldsmith LA, Viljoen D, Figuera LE, Fuchs W, Lebwohl M, Uitto J, Richards R, Hohl D, Ramesar R. A 500-kb region on chromosome 16p13.1 contains the pseudoxanthoma elasticum locus: high-resolution mapping and genomic structure. J Mol Med (Berl). 2000;78:36–46.CrossRefGoogle Scholar
  78. 78.
    le Sage C, Nagel R, Agami R. Diverse ways to control p27Kip1 function: miRNAs come into play. Cell Cycle. 2007;6:2742–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Fujita M, Yamada C, Goto H, Yokoyama N, Kuzushima K, Inagaki M, Tsurumi T. Cell cycle regulation of human CDC6 protein. Intracellular localization, interaction with the human mcm complex, and CDC2 kinase-mediated hyperphosphorylation. J Biol Chem. 1999;274:25927–32.PubMedCrossRefGoogle Scholar
  80. 80.
    Madine MA, Khoo CY, Mills AD, Laskey RA. MCM3 complex required for cell cycle regulation of DNA replication in vertebrate cells. Nature. 1995;375:421–4.PubMedCrossRefGoogle Scholar
  81. 81.
    Wilkinson KD. The discovery of ubiquitin-dependent proteolysis. Proc Natl Acad Sci U S A. 2005;102:15280–2.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Kimura Y, Tanaka K. Regulatory mechanisms involved in the control of ubiquitin homeostasis. J Biochem. 2010;147:793–8.PubMedCrossRefGoogle Scholar
  83. 83.
    Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev. 2002;82:373–428.PubMedCrossRefGoogle Scholar
  84. 84.
    Peters JM, Franke WW, Kleinschmidt JA. Distinct 19 S and 20 S subcomplexes of the 26 S proteasome and their distribution in the nucleus and the cytoplasm. J Biol Chem. 1994;269:7709–18.PubMedGoogle Scholar
  85. 85.
    Ardley HC, Robinson PA. E3 ubiquitin ligases. Essays Biochem. 2005;41:15–30.PubMedCrossRefGoogle Scholar
  86. 86.
    Bloom J, Amador V, Bartolini F, DeMartino G, Pagano M. Proteasome-mediated degradation of p21 via N-terminal ubiquitinylation. Cell. 2003;115:71–82.PubMedCrossRefGoogle Scholar
  87. 87.
    Chang L, Zhang Z, Yang J, McLaughlin SH, Barford D. Molecular architecture and mechanism of the anaphase-promoting complex. Nature. 2014;513:388–93.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Goldenberg SJ, Cascio TC, Shumway SD, Garbutt KC, Liu J, Xiong Y, Zheng N. Structure of the Cand1-Cul1-Roc1 complex reveals regulatory mechanisms for the assembly of the multisubunit Cullin-dependent ubiquitin ligases. Cell. 2004;119:517–28.PubMedCrossRefGoogle Scholar
  89. 89.
    Zheng N, Schulman BA, Song L, Miller JJ, Jeffrey PD, Wang P, Chu C, Koepp DM, Elledge SJ, Pagano M, Conaway RC, Conaway JW, Harper JW, Pavletich NP. Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature. 2002;416:703–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Lisztwan J, Marti A, Sutterluty H, Gstaiger M, Wirbelauer C, Krek W. Association of human CUL-1 and ubiquitin-conjugating enzyme CDC34 with the F-box protein p45(SKP2): evidence for evolutionary conservation in the subunit composition of the CDC34-SCF pathway. EMBO J. 1998;17:368–83.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Tsukada Y, Hirai H. Alpha-fetoprotein and albumin synthesis during the cell cycle. Ann N Y Acad Sci. 1975;259:37–44.PubMedCrossRefGoogle Scholar
  92. 92.
    Sell S, Skelly H, Leffert HL, Muller-Eberhard U, Kida S. Relationship of the biosynthesis of alpha-fetoprotein, albumin, hemopexin, and haptoglobin to the growth state of fetal rat hepatocyte cultures. Ann N Y Acad Sci. 1975;259:45–58.PubMedCrossRefGoogle Scholar
  93. 93.
    Tuczek HV, Fritz P, Wagner T, Grau A, Braun U, Wegner G. Investigations concerning the correlation between liver cell proliferation, production of alpha-fetoprotein, and DNA-synthesis of lymphocytes in the spleen of NMRI-mice. An autoradiographic and immunohistochemical study. Pathol Res Pract. 1984;178:335–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Tuczek HV, Fritz P, Wagner T, Braun U, Grau A, Wegner G. Synthesis of alpha-fetoprotein (AFP) and cell proliferation in regenerating livers of NMRI mice after partial hepatectomy. An immunohistochemical and autoradiographic study with 3H-thymidine. Virchows Arch B Cell Pathol Incl Mol Pathol. 1981;38:229–37.PubMedCrossRefGoogle Scholar
  95. 95.
    Sasaki K, Murakami T, Kawasaki S, Okita K, Takemoto T, Takahashi M. Change of alpha-fetoprotein content during cell cycle of human hepatoma cells in vitro: flow cytometric analysis. Tumour Biol. 1986;6:483–9.PubMedGoogle Scholar
  96. 96.
    Iida H, Honda M, Kawai HF, Yamashita T, Shirota Y, Wang BC, Miao H, Kaneko S. Ephrin-A1 expression contributes to the malignant characteristics of {alpha}-fetoprotein producing hepatocellular carcinoma. Gut. 2005;54:843–51.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Tang H, Tang XY, Liu M, Li X. Targeting alpha-fetoprotein represses the proliferation of hepatoma cells via regulation of the cell cycle. Clin Chim Acta. 2008;394:81–8.PubMedCrossRefGoogle Scholar
  98. 98.
    Li MS, Li PF, Li G, Du GG. Enhancement of proliferation of HeLa cells by the alpha-fetoprotein. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2002;34:769–74.Google Scholar
  99. 99.
    Allen RP, Ledford BE. The influence of antisera specific for alpha-fetoprotein and mouse serum albumin on the viability and protein synthesis of cultured mouse hepatoma cells. Cancer Res. 1977;37:696–701.PubMedGoogle Scholar
  100. 100.
    Ohkawa K, Tsukada Y, Hirai H. Effect of antibody to rat alpha-fetoprotein (AFP) on protein and DNA synthesis of rat ascites hepatoma AH66 cells. Gan To Kagaku Ryoho. 1984;11:227–34.PubMedGoogle Scholar
  101. 101.
    Zeleny M, Navratilova A, Kamycek Z, Vlk Z. Relation of hearing disorders to the acoustic composition of the working environment of musicians in a wind orchestra. Cesk Otolaryngol. 1975;24:295–9.PubMedGoogle Scholar
  102. 102.
    Yano H, Basaki Y, Oie S, Ogasawara S, Momosaki S, Akiba J, Nishida N, Kojiro S, Ishizaki H, Moriya F, Kuratomi K, Fukahori S, Kuwano M, Kojiro M. Effects of IFN-alpha on alpha-fetoprotein expressions in hepatocellular carcinoma cells. J Interf Cytokine Res. 2007;27:231–8.CrossRefGoogle Scholar
  103. 103.
    Cook JR, Schwartz CE, Fausel ED, Chiu JF. Effect of sodium butyrate on alpha-fetoprotein gene expression in rat hepatoma cells in vitro. Cancer Res. 1985;45:3215–9.PubMedGoogle Scholar
  104. 104.
    Hida D, Nakata K, Shima Y, Migita K, Nakao K, Kato Y, Ishii N, Eguchi K. Suppression of albumin and alpha-fetoprotein gene expression by butyrolactone I, a selective inhibitor of the cdk family, in HuH-7 human hepatoma cells. Anticancer Res. 1998;18:4317–22.PubMedGoogle Scholar
  105. 105.
    Motavaf M, Safari S, Saffari Jourshari M, Alavian SM. Hepatitis B virus-induced hepatocellular carcinoma: the role of the virus × protein. Acta Virol. 2013;57:389–96.PubMedCrossRefGoogle Scholar
  106. 106.
    Zhu M, Guo J, Li W, Lu Y, Fu S, Xie X, Xia H, Dong X, Chen Y, Quan M, Zheng S, Xie K, Li M. Hepatitis B virus X protein induces expression of alpha-fetoprotein and activates PI3K/mTOR signaling pathway in liver cells. Oncotarget 2015;Google Scholar
  107. 107.
    Zhang C, Chen X, Liu H, Li H, Jiang W, Hou W, McNutt MA, Lu F, Li G. Alpha fetoprotein mediates HBx induced carcinogenesis in the hepatocyte cytoplasm. Int J Cancer. 2015;Google Scholar
  108. 108.
    Minor MM, Slagle BL. Hepatitis B virus HBx protein interactions with the ubiquitin proteasome system. Viruses. 2014;6:4683–702.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Saxena N, Kumar V. The HBx oncoprotein of hepatitis B virus deregulates the cell cycle by promoting the intracellular accumulation and re-compartmentalization of the cellular deubiquitinase USP37. PLoS One. 2014;9:e111256.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Muehlemann M, Miller KD, Dauphinee M, Mizejewski GJ. Review of growth inhibitory peptide as a biotherapeutic agent for tumor growth, adhesion, and metastasis. Cancer Metastasis Rev. 2005;24:441–67.PubMedCrossRefGoogle Scholar
  111. 111.
    Mizejewski GJ, MacColl R. Alpha-fetoprotein growth inhibitory peptides: potential leads for cancer therapeutics. Mol Cancer Ther. 2003;2:1243–55.PubMedGoogle Scholar
  112. 112.
    Mizejewski GJ. The alpha-fetoprotein-derived growth inhibitory peptide 8-mer fragment: review of a novel anticancer agent. Cancer Biother Radiopharm. 2007;22:73–98.PubMedCrossRefGoogle Scholar
  113. 113.
    Mizejewski GJ, King M, Wonderlin WF, Wondergem R, Arcaro K. Cancer cell targeted delivery of growth inhibitory peptides derived from alpha-fetoprotein: review of an international multi-center collaborative study. Troy, NY: New Frontiers in Breast Cancer Research and Prevention; 2010. p. 8.Google Scholar
  114. 114.
    Turk C, Wong CH, Gozgit JM, Fagen-Solis K, Mizejewski GJ, Arcaro JM. Alpha-fetoprotein-derived peptide decreases cyclin-E expression, and p27 (KIP1) degradation in MCF-7 breast cancer cells. Troy, NY: Conference on Cancer Genomics; 2008. p. 29.Google Scholar
  115. 115.
    Turk C, Wong C, Gozgit JM, Muehlemann M, Reece MT, Mizejewski JJ, Arcaro KF. Alpha-fetoprotein derived growth inhibitory peptide (GIP) inhibits expression of cyclin E1. Proc Amer Assoc Cancer Res. 2006;47:66.Google Scholar
  116. 116.
    Sierralta WD, Epunan MJ, Reyes JM, Valladares LE, Pino AM. A synthetic peptide derived from alpha-fetoprotein inhibits the estradiol-induced proliferation of mammary tumor cells in culture through the modulation of p21. Adv Exp Med Biol. 2008;617:463–8.PubMedCrossRefGoogle Scholar
  117. 117.
    Mizejewski GJ. Alpha-fetoprotein (AFP) third domain fragments: Mapping AFP interaction sites with selective and non-selective cation channels. Current Topics in Peptide and Protein Research. 2016;(in press):Google Scholar
  118. 118.
    Mizejewski GJ. Review of third domain receptor binding fragment of AFP: plausible binding to lysophosliplipid receptor target. Curr Drug Targets. (in press);Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  1. 1.Division of Translational MedicineWadsworth Center, New York State Department of HealthAlbanyUSA

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