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PMID: 8612584 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

HTLV-1 Tax protein interacts with cyclin-dependent kinase inhibitor p16INK4A and counteracts its inhibitory activity towards CDK4.

The EMBO journal ·Vol. 15 ·No. 7 ·1996-04-01 ·Pages 1607-14

Suzuki T, Kitao S, Matsushime H, Yoshida M

Abstract

Tax, a regulatory protein of human T-cell leukemia virus type 1 (HTLV-1), is an oncoprotein which immortalizes human T cells and induces tumors in transgenic mice. These effects may be due to its interaction with cellular proteins, consisting of several transcription factors including CREB, NF-kappa B and SRF, and the transcriptional inhibitor, I kappa B. Here, we found that Tax binds to a cyclin-dependent kinase inhibitor, p16INK4A, which has ankyrin motifs similar to I kappa B. p16INK4A binds to the cyclin-dependent kinases, CDK4 and CDK6, and inhibits their activity, resulting in suppression of G1 phase progression. The binding of Tax to p16INK4a induced a reduction in the p16INK4A-CDK4 complex, with subsequent activation of CDK4 kinase. Tax also suppressed p16INK4A-mediated inhibition of U2OS cell growth. The p16INK4A gene was frequently deleted in many T-cell lines, but not in HTLV-1-infected T-cell lines. Taking these findings together, the functional inactivation of p16INK4A by Tax through protein-protein interaction is suggested to contribute to cellular immortalization and transformation induced by HTLV-1 infection.

MeSH Terms
Animals Base Sequence Binding Sites Carrier Proteins/genetics,metabolism Cell Cycle Cell Line Cell Transformation, Viral Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase Inhibitor p16 Cyclin-Dependent Kinases/antagonists & inhibitors DNA Primers/genetics Enzyme Inhibitors/metabolism Gene Products, tax/genetics,metabolism HTLV-I Infections/genetics,metabolism,virology Human T-lymphotropic virus 1/genetics,metabolism,pathogenicity Humans Mice Mice, Transgenic Molecular Sequence Data Proto-Oncogene Proteins Signal Transduction T-Lymphocytes
Chemicals
Carrier Proteins Cyclin-Dependent Kinase Inhibitor p16 DNA Primers Enzyme Inhibitors Gene Products, tax Proto-Oncogene Proteins CDK4 protein, human Cdk4 protein, mouse Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Suzuki T
Department of Cellular and Molecular Biology, University of Tokyo, Japan.
Kitao S
Matsushime H
Yoshida M
References (60)
60 references, click to expand
  1. Human T-cell leukemia virus type I Tax associates with and is negatively regulated by the NF-kappa B2 p100 gene product: implications for viral latency.
    Mol Cell Biol. 1994 Feb;14(2):1374-82 PMID: 8289813
  2. Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function.
    Genes Dev. 1994 Dec 15;8(24):2939-52 PMID: 8001816
  3. Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system.
    Mol Cell Biol. 1994 Mar;14(3):1669-79 PMID: 8114703
  4. D-type cyclin-dependent kinase activity in mammalian cells.
    Mol Cell Biol. 1994 Mar;14(3):2066-76 PMID: 8114738
  5. Identification of G1 kinase activity for cdk6, a novel cyclin D partner.
    Mol Cell Biol. 1994 Mar;14(3):2077-86 PMID: 8114739
  6. HTLV-1 Tax: regulation of gene expression and disease.
    Trends Microbiol. 1993 Jul;1(4):131-5 PMID: 8143128
  7. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers.
    Nature. 1994 Apr 21;368(6473):753-6 PMID: 8152487
  8. A cell cycle regulator potentially involved in genesis of many tumor types.
    Science. 1994 Apr 15;264(5157):436-40 PMID: 8153634
  9. Tax protein of human T-cell leukemia virus type I binds to the ankyrin motifs of inhibitory factor kappa B and induces nuclear translocation of transcription factor NF-kappa B proteins for transcriptional activation.
    Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3584-8 PMID: 8170951
  10. Tumor suppressor genes.
    Curr Opin Genet Dev. 1994 Feb;4(1):135-41 PMID: 8193533
  11. Human T cell lymphotropic virus type I-induced T cell activation. Resistance to TGF-beta 1-induced suppression.
    J Immunol. 1994 Jul 15;153(2):566-73 PMID: 8021495
  12. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.
    Nature. 1994 Sep 15;371(6494):257-61 PMID: 8078588
  13. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma.
    Proc Natl Acad Sci U S A. 1980 Dec;77(12):7415-9 PMID: 6261256
  14. Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease.
    Proc Natl Acad Sci U S A. 1982 Mar;79(6):2031-5 PMID: 6979048
  15. Identification of a protein (p40x) encoded by a unique sequence pX of human T-cell leukemia virus type I.
    Gan. 1984 Sep;75(9):747-51 PMID: 6094295
  16. The tat gene of human T-lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice.
    Science. 1987 Sep 11;237(4820):1324-9 PMID: 2888190
  17. Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase.
    Gene. 1988 Jul 15;67(1):31-40 PMID: 3047011
  18. Cellular targets for transformation by the adenovirus E1A proteins.
    Cell. 1989 Jan 13;56(1):67-75 PMID: 2521301
  19. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product.
    Science. 1989 Feb 17;243(4893):934-7 PMID: 2537532
  20. Electroporation: application to human lymphoid cell lines for stable introduction of a transactivator gene of human T-cell leukemia virus type I.
    Nucleic Acids Res. 1989 Feb 25;17(4):1589-604 PMID: 2784206
  21. Analysis of cDNA for human erythrocyte ankyrin indicates a repeated structure with homology to tissue-differentiation and cell-cycle control proteins.
    Nature. 1990 Mar 1;344(6261):36-42 PMID: 2137557
  22. Role of human T-cell leukemia virus type 1 X region proteins in immortalization of primary human lymphocytes in culture.
    J Virol. 1992 Jul;66(7):4570-5 PMID: 1351105
  23. Human T-cell lymphotropic virus type I (HTLV-I) transcriptional activator, Tax, enhances CREB binding to HTLV-I 21-base-pair repeats by protein-protein interaction.
    Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7070-4 PMID: 1386673
  24. Transcriptional activator Tax of HTLV-1 binds to the NF-kappa B precursor p105.
    Oncogene. 1992 Sep;7(9):1737-42 PMID: 1501885
  25. E2F: a link between the Rb tumor suppressor protein and viral oncoproteins.
    Science. 1992 Oct 16;258(5081):424-9 PMID: 1411535
  26. Interaction of HTLV-1 Tax1 with p67SRF causes the aberrant induction of cellular immediate early genes through CArG boxes.
    Genes Dev. 1992 Nov;6(11):2066-76 PMID: 1427072
  27. Assignment of a locus for familial melanoma, MLM, to chromosome 9p13-p22.
    Science. 1992 Nov 13;258(5085):1148-52 PMID: 1439824
  28. Structural and functional analysis of oncogenes and tumor suppressor genes in adult T-cell leukemia/lymphoma shows frequent p53 mutations.
    Blood. 1992 Dec 15;80(12):3205-16 PMID: 1361372
  29. The trans-activator tax of human T-cell leukemia virus type 1 (HTLV-1) interacts with cAMP-responsive element (CRE) binding and CRE modulator proteins that bind to the 21-base-pair enhancer of HTLV-1.
    Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):610-4 PMID: 8421695
  30. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins.
    Cell. 1993 May 7;73(3):487-97 PMID: 8343202
  31. Physical interaction of the retinoblastoma protein with human D cyclins.
    Cell. 1993 May 7;73(3):499-511 PMID: 8490963
  32. Cyclin D1 is a nuclear protein required for cell cycle progression in G1.
    Genes Dev. 1993 May;7(5):812-21 PMID: 8491378
  33. Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts.
    Genes Dev. 1993 Aug;7(8):1559-71 PMID: 8339933
  34. Cyclins and cyclin-dependent kinases: take your partners.
    Trends Biochem Sci. 1993 Jun;18(6):195-7 PMID: 8346551
  35. A trans-activator Tax of human T-cell leukemia virus type 1 binds to NF-kappa B p50 and serum response factor (SRF) and associates with enhancer DNAs of the NF-kappa B site and CArG box.
    Oncogene. 1993 Sep;8(9):2391-7 PMID: 8361755
  36. Inhibition of ras-induced proliferation and cellular transformation by p16INK4.
    Science. 1995 Jan 13;267(5195):249-52 PMID: 7809631
  37. HTLV-1 Tax enhances NF-kappa B2 expression and binds to the products p52 and p100, but does not suppress the inhibitory function of p100.
    Virology. 1995 Feb 1;206(2):1066-74 PMID: 7856081
  38. Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product.
    EMBO J. 1995 Feb 1;14(3):503-11 PMID: 7859739
  39. Development of leukemia in mice transgenic for the tax gene of human T-cell leukemia virus type I.
    Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):1057-61 PMID: 7862633
  40. Tumor suppression. Lessons in p16 from phylum Falconium.
    Curr Biol. 1995 Jan 1;5(1):28-31 PMID: 7697342
  41. Tax protein of HTLV-1 destabilizes the complexes of NF-kappa B and I kappa B-alpha and induces nuclear translocation of NF-kappa B for transcriptional activation.
    Oncogene. 1995 Mar 16;10(6):1199-207 PMID: 7700645
  42. Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6.
    Mol Cell Biol. 1995 May;15(5):2672-81 PMID: 7739547
  43. Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4.
    Mol Cell Biol. 1995 May;15(5):2682-8 PMID: 7739548
  44. Inhibitors of mammalian G1 cyclin-dependent kinases.
    Genes Dev. 1995 May 15;9(10):1149-63 PMID: 7758941
  45. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16.
    Nature. 1995 Jun 8;375(6531):503-6 PMID: 7777060
  46. Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition.
    Nature. 1995 Jun 8;375(6531):506-10 PMID: 7777061
  47. Growth suppression by p16ink4 requires functional retinoblastoma protein.
    Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6289-93 PMID: 7603984
  48. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs).
    Oncogene. 1995 Jul 20;11(2):211-9 PMID: 7624138
  49. HTLV-I encoded Tax in association with NF-kappa B precursor p105 enhances nuclear localization of NF-kappa B p50 and p65 in transfected cells.
    Oncogene. 1993 Nov;8(11):2949-58 PMID: 8414497
  50. Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas.
    Cancer Res. 1993 Nov 15;53(22):5535-41 PMID: 8221695
  51. The I kappa B proteins: multifunctional regulators of Rel/NF-kappa B transcription factors.
    Genes Dev. 1993 Nov;7(11):2064-70 PMID: 8224838
  52. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.
    Nature. 1993 Dec 16;366(6456):704-7 PMID: 8259215
  53. Homozygous loss of the cyclin-dependent kinase 4-inhibitor (p16) gene in human leukemias.
    Blood. 1994 Oct 15;84(8):2431-5 PMID: 7919362
  54. Tax protein of HTLV-1 interacts with the Rel homology domain of NF-kappa B p65 and c-Rel proteins bound to the NF-kappa B binding site and activates transcription.
    Oncogene. 1994 Nov;9(11):3099-105 PMID: 7936632
  55. Absence of p16INK4 protein is restricted to the subset of lung cancer lines that retains wildtype RB.
    Oncogene. 1994 Nov;9(11):3375-8 PMID: 7936665
  56. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age.
    Cell. 1994 Nov 18;79(4):573-82 PMID: 7954824
  57. Mutations and altered expression of p16INK4 in human cancer.
    Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11045-9 PMID: 7972006
  58. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus.
    Nat Genet. 1994 Sep;8(1):23-6 PMID: 7987388
  59. CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas.
    Cancer Res. 1994 Dec 15;54(24):6321-4 PMID: 7987821
  60. Overproduction of NFKB2 (lyt-10) and c-Rel: a mechanism for HTLV-I Tax-mediated trans-activation via the NF-kappa B signalling pathway.
    Oncogene. 1994 Mar;9(3):841-52 PMID: 8108127
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1996-04-01
Pages
1607-14
Language
English
Region
England
NLM ID
8208664
PMCID
PMC450070
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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