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PMID: 17548807 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 104 ·No. 24 ·2007-06-12 ·Pages 10175-80

Kuraishy AI, French SW, Sherman M, Herling M, Jones D, Wall R, Teitell MA

Abstract

Aberrant expression of the TCL1 oncoprotein promotes malignant transformation of germinal center (GC) B cells. Repression of TCL1 in GC B cells facilitates FAS-mediated apoptosis and prevents lymphoma formation. However, the mechanism for this repression is unknown. Here we show that the CREB coactivator TORC2 directly regulates TCL1 expression independent of CREB Ser-133 phosphorylation and CBP/p300 recruitment. GC signaling through CD40 or the BCR, which activates pCREB-dependent genes, caused TORC2 phosphorylation, cytosolic emigration, and TCL1 repression. Signaling via cAMP-inducible pathways inhibited TCL1 repression and reduced apoptosis, consistent with a prosurvival role for TCL1 before GC selection and supporting an initiating role for aberrant TCL1 expression during GC lymphomagenesis. Our data indicate that a novel CREB/TORC2 regulatory mode controls the normal program of GC gene activation and repression that promotes B cell development and circumvents oncogenic progression. Our results also reconcile a paradox in which signals that activate pCREB/CBP/p300 genes concurrently repress TCL1 to initiate its silencing.

MeSH Terms
Apoptosis B-Lymphocytes/immunology,metabolism,pathology Cell Line Cell Line, Tumor Cell Transformation, Neoplastic/genetics Gene Expression Regulation, Neoplastic Genetic Vectors Germinal Center/metabolism,pathology Humans Jurkat Cells Models, Biological Plasmids Proto-Oncogene Proteins/genetics,metabolism Retroviridae/genetics Signal Transduction Transcription Factors/genetics,metabolism Transcriptional Activation
Chemicals
CRTC2 protein, human Proto-Oncogene Proteins TCL1A protein, human Transcription Factors
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Kuraishy Ali I
Department of Human Genetics, and Jonsson Comprehensive Cancer Center, University of California-Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
French Samuel W
Sherman Mara
Herling Marco
Jones Dan
Wall Randolph
Teitell Michael A
References (52)
52 references, click to expand
  1. Sp1 transactivation of the TCL1 oncogene.
    J Biol Chem. 2003 Jan 10;278(2):948-55 PMID: 12421830
  2. Dysregulated TCL1 promotes multiple classes of mature B cell lymphoma.
    Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14392-7 PMID: 12381789
  3. T cell leukemia I oncogene expression depends on the presence of Epstein-Barr virus in the virus-carrying Burkitt lymphoma lines.
    Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4813-8 PMID: 12672960
  4. TORCs: transducers of regulated CREB activity.
    Mol Cell. 2003 Aug;12(2):413-23 PMID: 14536081
  5. OCA-B regulation of B-cell development and function.
    Trends Immunol. 2003 Oct;24(10):546-53 PMID: 14552839
  6. Textbook germinal centers?
    J Immunol. 2004 Mar 15;172(6):3369-75 PMID: 15004133
  7. B cell receptor-induced cAMP-response element-binding protein activation in B lymphocytes requires novel protein kinase Cdelta.
    J Biol Chem. 2004 Jul 16;279(29):30123-32 PMID: 15138267
  8. Mechanisms of B cell receptor induced apoptosis.
    Apoptosis. 2004 Sep;9(5):525-31 PMID: 15314280
  9. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector.
    Cell. 2004 Oct 1;119(1):61-74 PMID: 15454081
  10. B-cell apoptosis induced by antigen receptor crosslinking is blocked by a T-cell signal through CD40.
    Nature. 1993 Aug 12;364(6438):645-8 PMID: 7688865
  11. Identification of the TCL1 gene involved in T-cell malignancies.
    Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12530-4 PMID: 7809072
  12. Protein kinase C mediates activation of nuclear cAMP response element-binding protein (CREB) in B lymphocytes stimulated through surface Ig.
    J Immunol. 1995 Feb 15;154(4):1717-23 PMID: 7836756
  13. Cellular origin of human B-cell lymphomas.
    N Engl J Med. 1999 Nov 11;341(20):1520-9 PMID: 10559454
  14. Inhibition of Fas-mediated apoptosis by the B cell antigen receptor through c-FLIP.
    Eur J Immunol. 2000 Jan;30(1):155-63 PMID: 10602037
  15. CD40 and adenosine A2 receptor agonist-cyclic adenosine monophosphate rescue B-cell antigen receptor-induced apoptosis through independent pathways and converge to prevent caspase activation.
    J Allergy Clin Immunol. 2000 Mar;105(3):522-31 PMID: 10719303
  16. Tcl1 enhances Akt kinase activity and mediates its nuclear translocation.
    Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3028-33 PMID: 10716693
  17. Regulation of TCL1 expression in B- and T-cell lymphomas and reactive lymphoid tissues.
    Cancer Res. 2000 Apr 15;60(8):2095-100 PMID: 10786666
  18. Role of OCA-B in 3'-IgH enhancer function.
    J Immunol. 2000 May 15;164(10):5306-12 PMID: 10799892
  19. The protooncogene TCL1 is an Akt kinase coactivator.
    Mol Cell. 2000 Aug;6(2):395-407 PMID: 10983986
  20. B-cell receptor and Fas-mediated signals for life and death.
    Immunol Rev. 2000 Aug;176:105-15 PMID: 11043771
  21. Germinal center reaction.
    Curr Opin Hematol. 2001 Jan;8(1):52-9 PMID: 11138628
  22. Inducible resistance to Fas-mediated apoptosis in B cells.
    Cell Res. 2000 Dec;10(4):245-66 PMID: 11191348
  23. LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes.
    Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):507-12 PMID: 11149950
  24. TCL1 oncogene expression in B cell subsets from lymphoid hyperplasia and distinct classes of B cell lymphoma.
    Lab Invest. 2001 Apr;81(4):555-64 PMID: 11304575
  25. Molecular mechanisms of transcriptional control of bcl-2 and c-myc in follicular and transformed lymphoma.
    Cancer Res. 2001 Jul 1;61(13):5202-6 PMID: 11431360
  26. Transcriptional regulation by the phosphorylation-dependent factor CREB.
    Nat Rev Mol Cell Biol. 2001 Aug;2(8):599-609 PMID: 11483993
  27. Protection against Fas-dependent Th1-mediated apoptosis by antigen receptor engagement in B cells.
    Nature. 1995 Mar 9;374(6518):163-5 PMID: 7533263
  28. Targeted mutation in the Fas gene causes hyperplasia in peripheral lymphoid organs and liver.
    Nat Genet. 1995 Nov;11(3):294-300 PMID: 7581453
  29. MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data.
    Nucleic Acids Res. 1995 Dec 11;23(23):4878-84 PMID: 8532532
  30. Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis.
    Mol Cell Biol. 1996 Oct;16(10):5546-56 PMID: 8816467
  31. Up-regulation of Bcl-xL expression protects CD40-activated human B cells from Fas-mediated apoptosis.
    Cell Immunol. 1996 Oct 10;173(1):149-54 PMID: 8871610
  32. Bcl-x protects primary B cells against Fas-mediated apoptosis.
    J Immunol. 1997 Nov 15;159(10):4834-9 PMID: 9366408
  33. Thymic expression of the transcription factor Nur77 rescues the T cell but not the B cell abnormality of gld/gld mice.
    J Immunol. 1998 Oct 15;161(8):4252-6 PMID: 9780200
  34. TCL1 oncogene expression in AIDS-related lymphomas and lymphoid tissues.
    Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9809-14 PMID: 10449776
  35. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells.
    Nature. 2004 Dec 2;432(7017):635-9 PMID: 15577913
  36. Regulation of plasma-cell development.
    Nat Rev Immunol. 2005 Mar;5(3):230-42 PMID: 15738953
  37. Mechanisms of B-cell lymphoma pathogenesis.
    Nat Rev Cancer. 2005 Apr;5(4):251-62 PMID: 15803153
  38. The role of CREB as a proto-oncogene in hematopoiesis and in acute myeloid leukemia.
    Cancer Cell. 2005 Apr;7(4):351-62 PMID: 15837624
  39. The TCL1 family of oncoproteins: co-activators of transformation.
    Nat Rev Cancer. 2005 Aug;5(8):640-8 PMID: 16056259
  40. CREB: the unindicted cancer co-conspirator.
    Trends Cell Biol. 2005 Sep;15(9):457-9 PMID: 16084096
  41. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism.
    Nature. 2005 Oct 20;437(7062):1109-11 PMID: 16148943
  42. Role of cyclic AMP response element binding protein in human leukemias.
    Cancer. 2005 Nov 1;104(9):1819-24 PMID: 16196046
  43. Dual role of the coactivator TORC2 in modulating hepatic glucose output and insulin signaling.
    Cell Metab. 2005 Nov;2(5):331-8 PMID: 16271533
  44. 14-3-3 cooperates with LKB1 to regulate the activity and localization of QSK and SIK.
    J Cell Sci. 2005 Dec 1;118(Pt 23):5661-73 PMID: 16306228
  45. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin.
    Science. 2005 Dec 9;310(5754):1642-6 PMID: 16308421
  46. Effect of rapamycin on mouse chronic lymphocytic leukemia and the development of nonhematopoietic malignancies in Emu-TCL1 transgenic mice.
    Cancer Res. 2006 Jan 15;66(2):915-20 PMID: 16424025
  47. TCL1 shows a regulated expression pattern in chronic lymphocytic leukemia that correlates with molecular subtypes and proliferative state.
    Leukemia. 2006 Feb;20(2):280-5 PMID: 16341048
  48. Global transcriptional coactivators CREB-binding protein and p300 are highly essential collectively but not individually in peripheral B cells.
    Blood. 2006 Jun 1;107(11):4407-16 PMID: 16424387
  49. Dysregulated TCL1 requires the germinal center and genome instability for mature B-cell transformation.
    Blood. 2006 Sep 15;108(6):1991-8 PMID: 16728701
  50. Identification of nerve growth factor-responsive element of the TCL1 promoter as a novel negative regulatory element.
    J Biol Chem. 2006 Sep 22;281(38):27753-64 PMID: 16835233
  51. Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181.
    Cancer Res. 2006 Dec 15;66(24):11590-3 PMID: 17178851
  52. Transcriptional analysis of the B cell germinal center reaction.
    Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2639-44 PMID: 12604779
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.0704170104
Published
2007-06-12
Epub
2007-00-04
Pages
10175-80
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1891214
Subset
IM
Grants
NIGMS NIH HHS · R43 GM085841 · United States
NCI NIH HHS · R01 CA107300 · United States
NCI NIH HHS · R01 CA090571 · United States
NIGMS NIH HHS · R01 GM073981 · United States
NIGMS NIH HHS · R01 GM040185 · United States
NIGMS NIH HHS · T32 GM007185 · United States
NIGMS NIH HHS · GM 040185 · United States
NIGMS NIH HHS · R44 GM085841 · United States
NCI NIH HHS · CA 90571 · United States
NCI NIH HHS · CA 107300 · United States
NIGMS NIH HHS · GM 85841 · United States
NIGMS NIH HHS · GM 073981 · United States
NIGMS NIH HHS · GM 07185 · United States
NEI NIH HHS · PN/EY 018228 · United States
External Links
PubMed source DOI: 10.1073/pnas.0704170104 PMC Full Text View journal details
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