Home LiteratureArticle Details
PMID: 24384817 Published · epublish English Journal Article Research Support, N.I.H., Extramural Review

MYC and transcription elongation.

Cold Spring Harbor perspectives in medicine ·Vol. 4 ·No. 1 ·2014-01-01 ·Pages a020990

Rahl PB, Young RA

Abstract

Most transcription factors specify the subset of genes that will be actively transcribed in the cell by stimulating transcription initiation at these genes, but MYC has a fundamentally different role. MYC binds E-box sites in the promoters of active genes and stimulates recruitment of the elongation factor P-TEFb and thus transcription elongation. Consequently, rather than specifying the set of genes that will be transcribed in any particular cell, MYC's predominant role is to increase the production of transcripts from active genes. This increase in the transcriptional output of the cell's existing gene expression program, called transcriptional amplification, has a profound effect on proliferation and other behaviors of a broad range of cells. Transcriptional amplification may reduce rate-limiting constraints for tumor cell proliferation and explain MYC's broad oncogenic activity among diverse tissues.

MeSH Terms
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics,metabolism Gene Amplification Gene Expression Regulation, Neoplastic Genes, myc/physiology Humans Promoter Regions, Genetic Proto-Oncogene Proteins c-myc/genetics,metabolism Repressor Proteins/genetics,metabolism Transcription Elongation, Genetic Transcription Factors/metabolism
Chemicals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors MNT protein, human Proto-Oncogene Proteins c-myc Repressor Proteins Transcription Factors
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Rahl Peter B
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142.
Young Richard A
References (115)
115 references, click to expand
  1. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells.
    Cell. 2012 Sep 28;151(1):68-79 PMID: 23021216
  2. A core MYC gene expression signature is prominent in basal-like breast cancer but only partially overlaps the core serum response.
    PLoS One. 2009 Aug 19;4(8):e6693 PMID: 19690609
  3. MYC-induced cancer cell energy metabolism and therapeutic opportunities.
    Clin Cancer Res. 2009 Nov 1;15(21):6479-83 PMID: 19861459
  4. Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins.
    EMBO J. 2004 Jul 21;23(14):2830-40 PMID: 15241468
  5. c-Myc blazing a trail of death: coupling of the mitochondrial and death receptor apoptosis pathways by c-Myc.
    Cell Cycle. 2007 Oct 15;6(20):2464-72 PMID: 17914284
  6. The Mediator complex and transcription elongation.
    Biochim Biophys Acta. 2013 Jan;1829(1):69-75 PMID: 22983086
  7. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4.
    Mol Cell. 2005 Aug 19;19(4):535-45 PMID: 16109377
  8. Energy regulation: HIF MXIes it up with the C-MYC powerhouse.
    Dev Cell. 2007 Jun;12(6):845-6 PMID: 17543856
  9. Defining mechanisms that regulate RNA polymerase II transcription in vivo.
    Nature. 2009 Sep 10;461(7261):186-92 PMID: 19741698
  10. p53 activates transcription by directing structural shifts in Mediator.
    Nat Struct Mol Biol. 2010 Jun;17(6):753-60 PMID: 20453859
  11. MYC as a regulator of ribosome biogenesis and protein synthesis.
    Nat Rev Cancer. 2010 Apr;10(4):301-9 PMID: 20332779
  12. Reflecting on 25 years with MYC.
    Nat Rev Cancer. 2008 Dec;8(12):976-90 PMID: 19029958
  13. Functions of myc:max in the control of cell proliferation and tumorigenesis.
    Int Rev Cytol. 2004;238:183-226 PMID: 15364199
  14. NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation.
    Cell. 1999 Apr 2;97(1):41-51 PMID: 10199401
  15. Hallmarks of cancer: the next generation.
    Cell. 2011 Mar 4;144(5):646-74 PMID: 21376230
  16. NF-kappaB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II.
    Mol Cell. 2001 Aug;8(2):327-37 PMID: 11545735
  17. c-Myc regulates transcriptional pause release.
    Cell. 2010 Apr 30;141(3):432-45 PMID: 20434984
  18. Cell-type independent MYC target genes reveal a primordial signature involved in biomass accumulation.
    PLoS One. 2011;6(10):e26057 PMID: 22039435
  19. c-Myc, Genomic Instability and Disease.
    Genome Dyn. 2006;1:171-190 PMID: 18724060
  20. Genome recognition by MYC.
    Cold Spring Harb Perspect Med. 2014 Feb 01;4(2): PMID: 24492846
  21. The Myc oncoprotein as a therapeutic target for human cancer.
    Semin Cancer Biol. 2006 Aug;16(4):318-30 PMID: 16934487
  22. Combined microarray analysis of small cell lung cancer reveals altered apoptotic balance and distinct expression signatures of MYC family gene amplification.
    Oncogene. 2006 Jan 5;25(1):130-8 PMID: 16116477
  23. Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells.
    Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):2876-81 PMID: 23382218
  24. FACT, a factor that facilitates transcript elongation through nucleosomes.
    Cell. 1998 Jan 9;92(1):105-16 PMID: 9489704
  25. Myc Regulation of mRNA Cap Methylation.
    Genes Cancer. 2010 Jun;1(6):576-579 PMID: 21170289
  26. Turning the tables: Myc activates Wnt in breast cancer.
    Cell Cycle. 2007 Nov 1;6(21):2625-7 PMID: 17726380
  27. c-Myc mediates activation of the cad promoter via a post-RNA polymerase II recruitment mechanism.
    J Biol Chem. 2001 Dec 21;276(51):48562-71 PMID: 11673469
  28. The ATM-related domain of TRRAP is required for histone acetyltransferase recruitment and Myc-dependent oncogenesis.
    Genes Dev. 2001 Jul 1;15(13):1619-24 PMID: 11445536
  29. Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo.
    J Biol Chem. 2001 Aug 24;276(34):31793-9 PMID: 11431468
  30. The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis.
    Nat Med. 2004 May;10(5):484-6 PMID: 15098029
  31. The cell cycle and Myc intersect with mechanisms that regulate pluripotency and reprogramming.
    Cell Stem Cell. 2009 Aug 7;5(2):141-9 PMID: 19664987
  32. Distinct thresholds govern Myc's biological output in vivo.
    Cancer Cell. 2008 Dec 9;14(6):447-57 PMID: 19061836
  33. Cellular MYCro economics: Balancing MYC function with MYC expression.
    Cold Spring Harb Perspect Med. 2013 Nov 01;3(11): PMID: 24186489
  34. Tat competes with CIITA for the binding to P-TEFb and blocks the expression of MHC class II genes in HIV infection.
    Immunity. 2000 Jan;12(1):61-70 PMID: 10661406
  35. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters.
    Science. 2008 Dec 19;322(5909):1845-8 PMID: 19056941
  36. Myc's broad reach.
    Genes Dev. 2008 Oct 15;22(20):2755-66 PMID: 18923074
  37. Mammalian mediator of transcriptional regulation and its possible role as an end-point of signal transduction pathways.
    Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8538-43 PMID: 9671713
  38. Dissection of transcriptional programmes in response to serum and c-Myc in a human B-cell line.
    Oncogene. 2005 Jan 13;24(3):520-4 PMID: 15516975
  39. Mad: a heterodimeric partner for Max that antagonizes Myc transcriptional activity.
    Cell. 1993 Jan 29;72(2):211-22 PMID: 8425218
  40. The Oscar-worthy role of Myc in apoptosis.
    Semin Cancer Biol. 2006 Aug;16(4):275-87 PMID: 16945552
  41. The mechanism of release of P-TEFb and HEXIM1 from the 7SK snRNP by viral and cellular activators includes a conformational change in 7SK.
    PLoS One. 2010 Aug 23;5(8):e12335 PMID: 20808803
  42. Controlling the elongation phase of transcription with P-TEFb.
    Mol Cell. 2006 Aug 4;23(3):297-305 PMID: 16885020
  43. The Warburg effect in 2012.
    Curr Opin Oncol. 2012 Jan;24(1):62-7 PMID: 22123234
  44. An extended Myc network contributes to glucose homeostasis in cancer and diabetes.
    Front Biosci (Landmark Ed). 2011 Jun 01;16:2206-23 PMID: 21622171
  45. Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development.
    Nat Cell Biol. 2005 Mar;7(3):295-302 PMID: 15723055
  46. A Mediator-responsive form of metazoan RNA polymerase II.
    Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9506-11 PMID: 16769904
  47. The transcriptional program of a human B cell line in response to Myc.
    Nucleic Acids Res. 2001 Jan 15;29(2):397-406 PMID: 11139609
  48. Apoptotic signaling by c-MYC.
    Oncogene. 2008 Oct 27;27(50):6462-72 PMID: 18955973
  49. An overview of MYC and its interactome.
    Cold Spring Harb Perspect Med. 2014 Jan 01;4(1):a014357 PMID: 24384812
  50. Transcriptional regulation and its misregulation in disease.
    Cell. 2013 Mar 14;152(6):1237-51 PMID: 23498934
  51. Selective inhibition of tumor oncogenes by disruption of super-enhancers.
    Cell. 2013 Apr 11;153(2):320-34 PMID: 23582323
  52. Transcriptional regulation by Pol II(G) involving mediator and competitive interactions of Gdown1 and TFIIF with Pol II.
    Mol Cell. 2012 Jan 13;45(1):51-63 PMID: 22244332
  53. Transcriptional amplification in tumor cells with elevated c-Myc.
    Cell. 2012 Sep 28;151(1):56-67 PMID: 23021215
  54. Facilitators and impediments of the pluripotency reprogramming factors' initial engagement with the genome.
    Cell. 2012 Nov 21;151(5):994-1004 PMID: 23159369
  55. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription.
    Mol Cell. 2005 Aug 19;19(4):523-34 PMID: 16109376
  56. The histone chaperone FACT: structural insights and mechanisms for nucleosome reorganization.
    J Biol Chem. 2011 May 27;286(21):18369-74 PMID: 21454601
  57. Myc, cell competition, and compensatory proliferation.
    Cancer Res. 2005 Aug 1;65(15):6485-7 PMID: 16061622
  58. Efficient release from promoter-proximal stall sites requires transcript cleavage factor TFIIS.
    Mol Cell. 2005 Jan 7;17(1):103-12 PMID: 15629721
  59. Myc: a weapon of mass destruction.
    Cell. 2004 Apr 16;117(2):153-6 PMID: 15084254
  60. Transcriptional activation by recruitment.
    Nature. 1997 Apr 10;386(6625):569-77 PMID: 9121580
  61. Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells.
    Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):535-40 PMID: 22203960
  62. Function of the c-Myc oncoprotein in chromatin remodeling and transcription.
    Biochim Biophys Acta. 2001 Mar 21;1471(3):M135-45 PMID: 11250069
  63. c-Myc: linking transformation and genomic instability.
    Curr Mol Med. 2008 Sep;8(6):446-58 PMID: 18781952
  64. Master transcription factors and mediator establish super-enhancers at key cell identity genes.
    Cell. 2013 Apr 11;153(2):307-19 PMID: 23582322
  65. A chromatin landmark and transcription initiation at most promoters in human cells.
    Cell. 2007 Jul 13;130(1):77-88 PMID: 17632057
  66. Mediator and post-recruitment regulation of RNA polymerase II.
    Transcription. 2011 Jan-Feb;2(1):28-31 PMID: 21326907
  67. RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo.
    Nat Genet. 2007 Dec;39(12):1512-6 PMID: 17994019
  68. RNA polymerase is poised for activation across the genome.
    Nat Genet. 2007 Dec;39(12):1507-11 PMID: 17994021
  69. AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells.
    Mol Cell Biol. 2007 Dec;27(24):8815-23 PMID: 17938200
  70. The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation.
    Nat Rev Genet. 2010 Nov;11(11):761-72 PMID: 20940737
  71. The role of Myc-induced protein synthesis in cancer.
    Cancer Res. 2009 Dec 1;69(23):8839-43 PMID: 19934336
  72. Phospho switch triggers Brd4 chromatin binding and activator recruitment for gene-specific targeting.
    Mol Cell. 2013 Mar 7;49(5):843-57 PMID: 23317504
  73. Ratcheting Myc.
    Cancer Cell. 2008 Dec 9;14(6):425-6 PMID: 19061831
  74. P-TEFb is a crucial co-factor for Myc transactivation.
    Cell Cycle. 2007 Aug 15;6(16):2031-7 PMID: 17700062
  75. Transcription-independent functions of MYC: regulation of translation and DNA replication.
    Nat Rev Mol Cell Biol. 2008 Oct;9(10):810-5 PMID: 18698328
  76. Evidence for an alternative glycolytic pathway in rapidly proliferating cells.
    Science. 2010 Sep 17;329(5998):1492-9 PMID: 20847263
  77. The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins.
    Cell. 1998 Aug 7;94(3):363-74 PMID: 9708738
  78. Myc and the cell cycle.
    Front Biosci. 1998 Feb 15;3:d250-68 PMID: 9468463
  79. The transcriptional and epigenomic foundations of ground state pluripotency.
    Cell. 2012 Apr 27;149(3):590-604 PMID: 22541430
  80. DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs.
    Genes Dev. 1998 Feb 1;12(3):343-56 PMID: 9450929
  81. Role of MYC in Medulloblastoma.
    Cold Spring Harb Perspect Med. 2013 Nov 01;3(11): PMID: 24186490
  82. Pausing of RNA polymerase II disrupts DNA-specified nucleosome organization to enable precise gene regulation.
    Cell. 2010 Nov 12;143(4):540-51 PMID: 21074046
  83. Myc regulates the transcription of the PRC2 gene to control the expression of developmental genes in embryonic stem cells.
    Mol Cell Biol. 2012 Feb;32(4):840-51 PMID: 22184065
  84. The c-Myc target gene network.
    Semin Cancer Biol. 2006 Aug;16(4):253-64 PMID: 16904903
  85. Functional association of Gdown1 with RNA polymerase II poised on human genes.
    Mol Cell. 2012 Jan 13;45(1):38-50 PMID: 22244331
  86. Global analysis of short RNAs reveals widespread promoter-proximal stalling and arrest of Pol II in Drosophila.
    Science. 2010 Jan 15;327(5963):335-8 PMID: 20007866
  87. Myc influences global chromatin structure.
    EMBO J. 2006 Jun 21;25(12):2723-34 PMID: 16724113
  88. c-Myc recruits P-TEFb for transcription, cellular proliferation and apoptosis.
    Oncogene. 2003 Aug 28;22(36):5707-11 PMID: 12944920
  89. c-Myc and eIF4F constitute a feedforward loop that regulates cell growth: implications for anticancer therapy.
    Cancer Res. 2009 Oct 1;69(19):7491-4 PMID: 19773439
  90. The Max network gone mad.
    Mol Cell Biol. 2001 Feb;21(3):691-702 PMID: 11154257
  91. Rethinking the Warburg effect with Myc micromanaging glutamine metabolism.
    Cancer Res. 2010 Feb 1;70(3):859-62 PMID: 20086171
  92. c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription.
    Nat Cell Biol. 2005 Mar;7(3):303-10 PMID: 15723053
  93. CDK8 is a positive regulator of transcriptional elongation within the serum response network.
    Nat Struct Mol Biol. 2010 Feb;17(2):194-201 PMID: 20098423
  94. A switch from Myc:Max to Mad:Max heterocomplexes accompanies monocyte/macrophage differentiation.
    Genes Dev. 1993 Nov;7(11):2110-9 PMID: 8224841
  95. Myc recruits P-TEFb to mediate the final step in the transcriptional activation of the cad promoter.
    J Biol Chem. 2002 Oct 18;277(42):40156-62 PMID: 12177005
  96. Myc pathways provoking cell suicide and cancer.
    Oncogene. 2003 Dec 8;22(56):9007-21 PMID: 14663479
  97. The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein.
    Trends Cell Biol. 2010 Jul;20(7):427-34 PMID: 20399660
  98. New Myc-anisms for DNA replication and tumorigenesis?
    Cancer Cell. 2007 Aug;12(2):102-3 PMID: 17692801
  99. Tumor angiogenesis: cause or consequence of cancer?
    Cancer Res. 2007 Aug 1;67(15):7059-61 PMID: 17671171
  100. Revisiting global gene expression analysis.
    Cell. 2012 Oct 26;151(3):476-82 PMID: 23101621
  101. Divergent transcription from active promoters.
    Science. 2008 Dec 19;322(5909):1849-51 PMID: 19056940
  102. Mnt, a novel Max-interacting protein is coexpressed with Myc in proliferating cells and mediates repression at Myc binding sites.
    Genes Dev. 1997 Jan 1;11(1):44-58 PMID: 9000049
  103. RNA polymerase II elongation control.
    Annu Rev Biochem. 2012;81:119-43 PMID: 22404626
  104. Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc.
    Science. 1991 Mar 8;251(4998):1211-7 PMID: 2006410
  105. The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc.
    Mol Cell Biol. 2000 Jan;20(2):556-62 PMID: 10611234
  106. Pol II waiting in the starting gates: Regulating the transition from transcription initiation into productive elongation.
    Biochim Biophys Acta. 2011 Jan;1809(1):34-45 PMID: 21081187
  107. Mediator MED23 regulates basal transcription in vivo via an interaction with P-TEFb.
    Transcription. 2013 Jan-Feb;4(1):39-51 PMID: 23340209
  108. Control of cell proliferation and growth by Myc proteins.
    Results Probl Cell Differ. 2006;42:329-42 PMID: 16903216
  109. Human mediator subunit MED26 functions as a docking site for transcription elongation factors.
    Cell. 2011 Jul 8;146(1):92-104 PMID: 21729782
  110. c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I.
    Nat Cell Biol. 2005 Mar;7(3):311-8 PMID: 15723054
  111. Crosstalk between c-Myc and ribosome in ribosomal biogenesis and cancer.
    J Cell Biochem. 2008 Oct 15;105(3):670-7 PMID: 18773413
  112. Myc-binding-site recognition in the human genome is determined by chromatin context.
    Nat Cell Biol. 2006 Jul;8(7):764-70 PMID: 16767079
  113. Subgroup-specific structural variation across 1,000 medulloblastoma genomes.
    Nature. 2012 Aug 2;488(7409):49-56 PMID: 22832581
  114. Facilitating replication under stress: an oncogenic function of MYC?
    Nat Rev Cancer. 2009 Jun;9(6):441-4 PMID: 19461668
  115. The molecular role of Myc in growth and transformation: recent discoveries lead to new insights.
    FASEB J. 1998 Jun;12(9):633-51 PMID: 9619443
Article Info
Journal
Cold Spring Harbor perspectives in medicine
Abbr.
Cold Spring Harb Perspect Med
ISSN
2157-1422
DOI
10.1101/cshperspect.a020990
Published
2014-01-01
Epub
2014-00-01
Pages
a020990
Language
English
Region
United States
NLM ID
101571139
PMCID
PMC3869279
Subset
IM
Grants
NCI NIH HHS · R01 CA146445 · United States
NHGRI NIH HHS · R01 HG002668 · United States
NCI NIH HHS · CA146445 · United States
NHGRI NIH HHS · HG002668 · United States
External Links
PubMed source DOI: 10.1101/cshperspect.a020990 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2