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PMID: 10377405 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Separation of C/EBPalpha-mediated proliferation arrest and differentiation pathways.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 13 ·1999-06-22 ·Pages 7276-81

Müller C, Alunni-Fabbroni M, Kowenz-Leutz E, Mo X, Tommasino M, Leutz A

Abstract

Cell proliferation and terminal differentiation are mutually exclusive in most cell lineages. The b-zip transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha) induces proliferation arrest and differentiation in many cell types, suggesting that both activities are linked. Here we show that C/EBPalpha-mediated proliferation arrest and differentiation pathways can be separated by the E7 oncoprotein of the "high-risk" human papilloma virus 16. The E7 oncoprotein overrides C/EBPalpha-mediated cell cycle withdrawal without compromising the transactivation activity of C/EBPalpha or its ability to participate in differentiation. Uncoupling of both pathways depends on the casein kinase II site of the oncoprotein but not on its ability to neutralize pocket proteins or the cyclin-dependent kinase inhibitor protein p21. Our results suggest a bifurcation of C/EBPalpha-mediated proliferation arrest and differentiation pathways.

MeSH Terms
Animals CCAAT-Enhancer-Binding Proteins Cell Differentiation/physiology Cell Division/physiology Cell Line Cell Lineage/physiology Cell Transformation, Viral DNA-Binding Proteins/physiology Fibroblasts/cytology,physiology Gene Expression Regulation/physiology Gene Transfer Techniques Humans Mice Mice, Inbred BALB C Nuclear Proteins/physiology Oncogene Proteins, Viral/physiology Papillomaviridae Papillomavirus E7 Proteins Transcription Factors/physiology
Chemicals
CCAAT-Enhancer-Binding Proteins DNA-Binding Proteins Nuclear Proteins Oncogene Proteins, Viral Papillomavirus E7 Proteins Transcription Factors oncogene protein E7, Human papillomavirus type 16
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Müller C
Max-Delbrück-Center for Molecular Medicine, 13092 Berlin, Germany.
Alunni-Fabbroni M
Kowenz-Leutz E
Mo X
Tommasino M
Leutz A
References (63)
63 references, click to expand
  1. Transcription factors C/EBP alpha, C/EBP beta, and CHOP (Gadd153) expressed during the differentiation program of keratinocytes in vitro and in vivo.
    J Invest Dermatol. 1998 Mar;110(3):238-46 PMID: 9506442
  2. CCAAT/enhancer binding protein alpha regulates p21 protein and hepatocyte proliferation in newborn mice.
    Mol Cell Biol. 1997 Dec;17(12):7353-61 PMID: 9372966
  3. Continuous tissue culture cell lines derived from chemically induced tumors of Japanese quail.
    Cell. 1977 May;11(1):95-103 PMID: 194709
  4. Induction of fatty acid synthetase synthesis in differentiating 3T3-L1 preadipocytes.
    J Biol Chem. 1980 May 25;255(10):4745-50 PMID: 7372608
  5. Cloning and sequencing of a deoxyribonucleic acid copy of glyceraldehyde-3-phosphate dehydrogenase messenger ribonucleic acid isolated from chicken muscle.
    Biochemistry. 1983 Mar 29;22(7):1605-13 PMID: 6303388
  6. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
    Anal Biochem. 1987 Apr;162(1):156-9 PMID: 2440339
  7. Construction and characterization of a retroviral vector demonstrating efficient expression of cloned cDNA sequences.
    DNA. 1988 Apr;7(3):219-25 PMID: 2836147
  8. 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
  9. A point mutational analysis of human papillomavirus type 16 E7 protein.
    J Virol. 1989 Jun;63(6):2650-6 PMID: 2542578
  10. Tissue-specific expression, developmental regulation, and genetic mapping of the gene encoding CCAAT/enhancer binding protein.
    Genes Dev. 1989 Aug;3(8):1146-56 PMID: 2792758
  11. Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product.
    EMBO J. 1989 Dec 20;8(13):4099-105 PMID: 2556261
  12. The v-myb oncogene product binds to and activates the promyelocyte-specific mim-1 gene.
    Cell. 1989 Dec 22;59(6):1115-25 PMID: 2688896
  13. CCAAT/enhancer binding protein activates the promoter of the serum albumin gene in cultured hepatoma cells.
    Genes Dev. 1989 Sep;3(9):1314-22 PMID: 2558052
  14. Differentiation-induced gene expression in 3T3-L1 preadipocytes: CCAAT/enhancer binding protein interacts with and activates the promoters of two adipocyte-specific genes.
    Genes Dev. 1989 Sep;3(9):1323-35 PMID: 2606350
  15. Mouse insulin-responsive glucose transporter gene: characterization of the gene and trans-activation by the CCAAT/enhancer binding protein.
    Proc Natl Acad Sci U S A. 1990 Jan;87(1):251-5 PMID: 2404278
  16. Is CCAAT/enhancer-binding protein a central regulator of energy metabolism?
    Genes Dev. 1989 Dec;3(12B):2021-4 PMID: 2697636
  17. A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family.
    EMBO J. 1990 Jun;9(6):1897-906 PMID: 2112087
  18. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line.
    Nucleic Acids Res. 1990 Jun 25;18(12):3587-96 PMID: 2194165
  19. CCAAT-enhancer binding protein: a component of a differentiation switch.
    Science. 1991 Jan 18;251(4991):288-92 PMID: 1987644
  20. The E7 protein of human papillomavirus type 16 is phosphorylated by casein kinase II.
    New Biol. 1989 Oct;1(1):44-53 PMID: 2562189
  21. Negative charge at the casein kinase II phosphorylation site is important for transformation but not for Rb protein binding by the E7 protein of human papillomavirus type 16.
    Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5187-91 PMID: 2052600
  22. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells.
    Genes Dev. 1991 Sep;5(9):1538-52 PMID: 1840554
  23. Viruses in human cancers.
    Science. 1991 Nov 22;254(5035):1167-73 PMID: 1659743
  24. Structure-function analysis of the human papillomavirus type 16 E7 oncoprotein.
    J Virol. 1992 Apr;66(4):2418-27 PMID: 1312637
  25. Identification of genes differentially expressed in two types of v-myb-transformed avian myelomonocytic cells.
    Oncogene. 1992 Mar;7(3):527-34 PMID: 1549365
  26. Antisense CCAAT/enhancer-binding protein RNA suppresses coordinate gene expression and triglyceride accumulation during differentiation of 3T3-L1 preadipocytes.
    Genes Dev. 1992 Apr;6(4):533-44 PMID: 1373117
  27. Reciprocal regulation of adipogenesis by Myc and C/EBP alpha.
    Science. 1992 Apr 17;256(5055):379-82 PMID: 1566086
  28. Growth-dependent inhibition of CCAAT enhancer-binding protein (C/EBP alpha) gene expression during hepatocyte proliferation in the regenerating liver and in culture.
    Mol Cell Biol. 1992 Jun;12(6):2553-60 PMID: 1588957
  29. IL-6 and NF-IL6 in acute-phase response and viral infection.
    Immunol Rev. 1992 Jun;127:25-50 PMID: 1380488
  30. A novel temporal expression pattern of three C/EBP family members in differentiating myelomonocytic cells.
    Blood. 1992 Oct 1;80(7):1725-35 PMID: 1391942
  31. Homologous sequences in adenovirus E1A and human papillomavirus E7 proteins mediate interaction with the same set of cellular proteins.
    J Virol. 1992 Dec;66(12):6893-902 PMID: 1331501
  32. The two C/EBP isoforms, IL-6DBP/NF-IL6 and C/EBP delta/NF-IL6 beta, are induced by IL-6 to promote acute phase gene transcription via different mechanisms.
    Nucleic Acids Res. 1993 Jan 25;21(2):289-94 PMID: 7680115
  33. Participation of the transcription factor C/EBP delta in the acute-phase regulation of the human gene for complement component C3.
    Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2584-8 PMID: 8385337
  34. Human papillomavirus type 16 E7 associates with a histone H1 kinase and with p107 through sequences necessary for transformation.
    J Virol. 1993 May;67(5):2521-8 PMID: 8386265
  35. Synergistic activation of the chicken mim-1 gene by v-myb and C/EBP transcription factors.
    EMBO J. 1993 May;12(5):2027-38 PMID: 8491193
  36. Myb and NF-M: combinatorial activators of myeloid genes in heterologous cell types.
    Genes Dev. 1993 May;7(5):749-59 PMID: 7684005
  37. Production of high-titer helper-free retroviruses by transient transfection.
    Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8392-6 PMID: 7690960
  38. Cell lineage-specific and differentiation-dependent patterns of CCAAT/enhancer binding protein alpha expression in the gut epithelium of normal and transgenic mice.
    Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8871-5 PMID: 8415623
  39. A 30-kDa alternative translation product of the CCAAT/enhancer binding protein alpha message: transcriptional activator lacking antimitotic activity.
    Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9606-10 PMID: 8415748
  40. Three levels of functional interaction determine the activity of CCAAT/enhancer binding protein-alpha on the serum albumin promoter.
    Genes Dev. 1994 Feb 1;8(3):350-62 PMID: 8314088
  41. C/EBP is an immediate-early gene required for the consolidation of long-term facilitation in Aplysia.
    Cell. 1994 Mar 25;76(6):1099-114 PMID: 8137425
  42. Functional studies of E7 proteins from different HPV types.
    Oncogene. 1994 Sep;9(9):2633-8 PMID: 8058327
  43. CCAAT/enhancer binding protein alpha is sufficient to initiate the 3T3-L1 adipocyte differentiation program.
    Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8757-61 PMID: 8090719
  44. Ectopic expression of the CCAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells.
    Genes Dev. 1994 Jul 15;8(14):1654-63 PMID: 7958846
  45. Novel mechanism of C/EBP beta (NF-M) transcriptional control: activation through derepression.
    Genes Dev. 1994 Nov 15;8(22):2781-91 PMID: 7958933
  46. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor.
    Cell. 1994 Dec 30;79(7):1147-56 PMID: 8001151
  47. Human papillomaviruses.
    Annu Rev Microbiol. 1994;48:427-47 PMID: 7826013
  48. Targeted disruption of the NF-IL6 gene discloses its essential role in bacteria killing and tumor cytotoxicity by macrophages.
    Cell. 1995 Jan 27;80(2):353-61 PMID: 7530603
  49. Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins.
    Genes Dev. 1995 Jan 15;9(2):168-81 PMID: 7531665
  50. Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice.
    EMBO J. 1995 May 1;14(9):1932-41 PMID: 7744000
  51. Impaired energy homeostasis in C/EBP alpha knockout mice.
    Science. 1995 Aug 25;269(5227):1108-12 PMID: 7652557
  52. Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal differentiated keratinocytes.
    Genes Dev. 1995 Oct 1;9(19):2335-49 PMID: 7557386
  53. Inhibition of cell proliferation by C/EBP alpha occurs in many cell types, does not require the presence of p53 or Rb, and is not affected by large T-antigen.
    Nucleic Acids Res. 1995 Nov 25;23(22):4726-33 PMID: 8524667
  54. Retinoblastoma protein directly interacts with and activates the transcription factor NF-IL6.
    Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):465-9 PMID: 8552662
  55. NF-M (chicken C/EBP beta) induces eosinophilic differentiation and apoptosis in a hematopoietic progenitor cell line.
    EMBO J. 1995 Dec 15;14(24):6127-35 PMID: 8557032
  56. CCAAT/enhancer-binding protein alpha (C/EBP alpha) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein.
    Genes Dev. 1996 Apr 1;10(7):804-15 PMID: 8846917
  57. The human papillomavirus type 16 E7 gene product interacts with and trans-activates the AP1 family of transcription factors.
    EMBO J. 1996 Apr 15;15(8):1950-60 PMID: 8617242
  58. HPV-16 E7 and adenovirus E1a complex formation with TATA box binding protein is enhanced by casein kinase II phosphorylation.
    Oncogene. 1996 Jun 6;12(11):2325-30 PMID: 8649772
  59. Retinoblastoma protein positively regulates terminal adipocyte differentiation through direct interaction with C/EBPs.
    Genes Dev. 1996 Nov 1;10(21):2794-804 PMID: 8946919
  60. Transcription factor C/EBPalpha: novel sites of expression and cloning of the human gene.
    Biol Chem. 1997 May;378(5):373-9 PMID: 9191024
  61. Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein.
    Genes Dev. 1997 Aug 15;11(16):2090-100 PMID: 9284048
  62. The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21Cip1-mediated inhibition of cdk2.
    Genes Dev. 1997 Aug 15;11(16):2101-11 PMID: 9284049
  63. An established preadipose cell line and its differentiation in culture. II. Factors affecting the adipose conversion.
    Cell. 1975 May;5(1):19-27 PMID: 165899
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.13.7276
Published
1999-06-22
Pages
7276-81
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC22076
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.96.13.7276 PMC Full Text View journal details
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