Home LiteratureArticle Details
PMID: 9742113 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

myc boxes, which are conserved in myc family proteins, are signals for protein degradation via the proteasome.

Molecular and cellular biology ·Vol. 18 ·No. 10 ·1998-10-00 ·Pages 5961-9

Flinn EM, Busch CM, Wright AP

Abstract

Cellular levels of the rapidly degraded c-myc protein play an important role in determining the proliferation status of cells. Increased levels of c-myc are frequently associated with rapidly proliferating tumor cells. We show here that myc boxes I and II, found in the N termini of all members of the myc protein family, function to direct the degradation of the c-myc protein. Both myc boxes I and II contain sufficient information to independently direct the degradation of otherwise stably expressed proteins to which they are fused. At least part of the myc box-directed degradation occurs via the proteasome. The mechanism of myc box-directed degradation appears to be conserved between yeast and mammalian cells. Our results suggest that the myc boxes may play an important role in regulating the level and activity of the c-myc protein.

MeSH Terms
Animals COS Cells Cysteine Endopeptidases/metabolism Multienzyme Complexes/metabolism Proteasome Endopeptidase Complex Proto-Oncogene Proteins c-myc/genetics,metabolism RNA, Messenger/metabolism Receptors, Glucocorticoid/genetics,metabolism
Chemicals
Multienzyme Complexes Proto-Oncogene Proteins c-myc RNA, Messenger Receptors, Glucocorticoid Cysteine Endopeptidases Proteasome Endopeptidase Complex
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Flinn E M
Karolinska Institute, Department of Biosciences, NOVUM, S-14157 Huddinge, Sweden. elizabeth.flinn@cbt.ki.se
Busch C M
Wright A P
References (75)
75 references, click to expand
  1. CCAAT/enhancer binding protein gene promoter: binding of nuclear factors during differentiation of 3T3-L1 preadipocytes.
    Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2593-7 PMID: 2006196
  2. 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
  3. Three proteolytic systems in the yeast saccharomyces cerevisiae.
    J Biol Chem. 1991 May 5;266(13):7963-6 PMID: 2022624
  4. What determines the instability of c-myc proto-oncogene mRNA?
    Bioessays. 1992 Feb;14(2):119-24 PMID: 1575711
  5. A new bind for Myc.
    Trends Genet. 1992 Mar;8(3):91-6 PMID: 1579994
  6. Transcriptional activation by the human c-Myc oncoprotein in yeast requires interaction with Max.
    Nature. 1992 Oct 1;359(6394):423-6 PMID: 1406955
  7. Regulation of proto-oncogene mRNA stability.
    Biochim Biophys Acta. 1992 Dec 16;1114(2-3):95-106 PMID: 1457466
  8. Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination.
    Nature. 1992 Dec 10;360(6404):597-9 PMID: 1334232
  9. Sequence-specific transcriptional activation by Myc and repression by Max.
    Mol Cell Biol. 1993 Jan;13(1):383-90 PMID: 8417337
  10. Transactivation of gene expression by Myc is inhibited by mutation at the phosphorylation sites Thr-58 and Ser-62.
    Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3216-20 PMID: 8386367
  11. Gene-regulatory properties of Myc helix-loop-helix/leucine zipper mutants: Max-dependent DNA binding and transcriptional activation in yeast correlates with transforming capacity.
    Oncogene. 1993 Jul;8(7):1849-55 PMID: 8510929
  12. An essential E box in the promoter of the gene encoding the mRNA cap-binding protein (eukaryotic initiation factor 4E) is a target for activation by c-myc.
    Mol Cell Biol. 1996 Sep;16(9):4754-64 PMID: 8756633
  13. Exon 2-mediated c-myc mRNA decay in vivo is independent of its translation.
    Mol Cell Biol. 1996 Sep;16(9):5107-16 PMID: 8756668
  14. Myc-Max heterodimers activate a DEAD box gene and interact with multiple E box-related sites in vivo.
    EMBO J. 1996 Aug 15;15(16):4344-57 PMID: 8861962
  15. Identification of downstream-initiated c-Myc proteins which are dominant-negative inhibitors of transactivation by full-length c-Myc proteins.
    Mol Cell Biol. 1997 Mar;17(3):1459-68 PMID: 9032273
  16. Coding elements in exons 2 and 3 target c-myc mRNA downregulation during myogenic differentiation.
    Mol Cell Biol. 1997 May;17(5):2698-707 PMID: 9111340
  17. Myc represses the growth arrest gene gadd45.
    Oncogene. 1997 Jun 12;14(23):2825-34 PMID: 9190899
  18. Covalent modification of the active site threonine of proteasomal beta subunits and the Escherichia coli homolog HslV by a new class of inhibitors.
    Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6629-34 PMID: 9192616
  19. Identification of putative c-Myc-responsive genes: characterization of rcl, a novel growth-related gene.
    Mol Cell Biol. 1997 Sep;17(9):4967-78 PMID: 9271375
  20. CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis.
    Science. 1997 Oct 17;278(5337):460-3 PMID: 9334304
  21. Targeting of substrates to the 26S proteasome.
    FASEB J. 1997 Nov;11(13):1055-66 PMID: 9367341
  22. In vivo degradation of N-myc in neuroblastoma cells is mediated by the 26S proteasome.
    Oncogene. 1998 Mar 5;16(9):1131-9 PMID: 9528855
  23. Transformation of intact yeast cells treated with alkali cations.
    J Bacteriol. 1983 Jan;153(1):163-8 PMID: 6336730
  24. Genomic sequencing.
    Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991-5 PMID: 6326095
  25. Proteins encoded by the human c-myc oncogene: differential expression in neoplastic cells.
    Mol Cell Biol. 1984 Nov;4(11):2486-97 PMID: 6513926
  26. The protein encoded by the human proto-oncogene c-myc.
    Proc Natl Acad Sci U S A. 1984 Dec;81(24):7742-6 PMID: 6393124
  27. Human N-myc is closely related in organization and nucleotide sequence to c-myc.
    Nature. 1986 Jan 2-8;319(6048):73-7 PMID: 3510398
  28. Nucleotide sequence of the human N-myc gene.
    Proc Natl Acad Sci U S A. 1986 Mar;83(6):1772-6 PMID: 2869488
  29. In vivo half-life of a protein is a function of its amino-terminal residue.
    Science. 1986 Oct 10;234(4773):179-86 PMID: 3018930
  30. Tissue-specific in vitro transcription from the mouse albumin promoter.
    Cell. 1986 Dec 5;47(5):767-76 PMID: 3779841
  31. TATA-binding protein and the retinoblastoma gene product bind to overlapping epitopes on c-Myc and adenovirus E1A protein.
    Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8489-93 PMID: 7690963
  32. Point mutations in the c-Myc transactivation domain are common in Burkitt's lymphoma and mouse plasmacytomas.
    Nat Genet. 1993 Sep;5(1):56-61 PMID: 8220424
  33. An embryonically expressed gene is a target for c-Myc regulation via the c-Myc-binding sequence.
    Genes Dev. 1992 Dec;6(12B):2513-23 PMID: 1340466
  34. Phosphorylation sites mapping in the N-terminal domain of c-myc modulate its transforming potential.
    Oncogene. 1993 Dec;8(12):3199-209 PMID: 8247524
  35. c-Myc induces the expression and activity of ornithine decarboxylase.
    Cell Growth Differ. 1993 Nov;4(11):879-83 PMID: 8297793
  36. Site-specific modulation of c-Myc cotransformation by residues phosphorylated in vivo.
    Oncogene. 1994 Jan;9(1):59-70 PMID: 8302604
  37. Ongoing mutations in the N-terminal domain of c-Myc affect transactivation in Burkitt's lymphoma cell lines.
    Oncogene. 1994 Mar;9(3):759-63 PMID: 8108117
  38. Binding and suppression of the Myc transcriptional activation domain by p107.
    Science. 1994 Apr 8;264(5156):251-4 PMID: 8146655
  39. Repression of cyclin D1: a novel function of MYC.
    Mol Cell Biol. 1994 Jun;14(6):4032-43 PMID: 8196642
  40. c-Myc represses transcription in vivo by a novel mechanism dependent on the initiator element and Myc box II.
    EMBO J. 1994 Sep 1;13(17):4070-9 PMID: 8076602
  41. Interaction of c-Myc with the pRb-related protein p107 results in inhibition of c-Myc-mediated transactivation.
    EMBO J. 1994 Sep 1;13(17):4080-6 PMID: 8076603
  42. Ubiquitin-dependent c-Jun degradation in vivo is mediated by the delta domain.
    Cell. 1994 Sep 9;78(5):787-98 PMID: 8087846
  43. The transactivation domain of Pho4 is required for nucleosome disruption at the PHO5 promoter.
    EMBO J. 1994 Oct 17;13(20):4856-62 PMID: 7957055
  44. Regulated degradation of the transcription factor Gcn4.
    EMBO J. 1994 Dec 15;13(24):6021-30 PMID: 7813440
  45. An essential domain of the c-myc protein interacts with a nuclear factor that is also required for E1A-mediated transformation.
    Mol Cell Biol. 1995 Mar;15(3):1536-44 PMID: 7862146
  46. Rapid protein extraction from Saccharomyces cerevisiae.
    Yeast. 1994 Oct;10(10):1305-10 PMID: 7900419
  47. The N-terminal domain of c-Myc associates with alpha-tubulin and microtubules in vivo and in vitro.
    Mol Cell Biol. 1995 Sep;15(9):5188-95 PMID: 7651436
  48. Mouse and rat B-myc share amino acid sequence homology with the c-myc transcriptional activator domain and contain a B-myc specific carboxy terminal region.
    Oncogene. 1995 Nov 16;11(10):1963-9 PMID: 7478514
  49. Identification of sequences in c-myc mRNA that regulate its steady-state levels.
    Mol Cell Biol. 1996 Jul;16(7):3511-22 PMID: 8668167
  50. Functional interaction of the c-Myc transactivation domain with the TATA binding protein: evidence for an induced fit model of transactivation domain folding.
    Biochemistry. 1996 Jul 23;35(29):9584-93 PMID: 8755740
  51. Cdc25 cell-cycle phosphatase as a target of c-myc.
    Nature. 1996 Aug 8;382(6591):511-7 PMID: 8700224
  52. PEST sequences and regulation by proteolysis.
    Trends Biochem Sci. 1996 Jul;21(7):267-71 PMID: 8755249
  53. Evolutionarily conserved regions of the human c-myc protein can be uncoupled from transforming activity.
    Proc Natl Acad Sci U S A. 1987 Jan;84(1):170-3 PMID: 3467348
  54. Definition of regions in human c-myc that are involved in transformation and nuclear localization.
    Mol Cell Biol. 1987 May;7(5):1697-709 PMID: 3299053
  55. Structure and expression of the murine L-myc gene.
    EMBO J. 1987 Nov;6(11):3359-66 PMID: 2828024
  56. Rapid and efficient site-specific mutagenesis without phenotypic selection.
    Methods Enzymol. 1987;154:367-82 PMID: 3323813
  57. DNA-bound Fos proteins activate transcription in yeast.
    Cell. 1988 Jan 29;52(2):179-84 PMID: 3124961
  58. A non-AUG translational initiation in c-myc exon 1 generates an N-terminally distinct protein whose synthesis is disrupted in Burkitt's lymphomas.
    Cell. 1988 Jan 29;52(2):185-95 PMID: 3277717
  59. c-myc and c-myb protein degradation: effect of metabolic inhibitors and heat shock.
    Mol Cell Biol. 1988 Jun;8(6):2504-12 PMID: 3043180
  60. Involvement of the 'leucine zipper' region in the oligomerization and transforming activity of human c-myc protein.
    Nature. 1989 Feb 16;337(6208):664-6 PMID: 2645525
  61. DNA-binding domain of human c-Myc produced in Escherichia coli.
    Mol Cell Biol. 1989 Jun;9(6):2477-86 PMID: 2668734
  62. Degradation of ornithine decarboxylase in mammalian cells is ATP dependent but ubiquitin independent.
    Eur J Biochem. 1989 Nov 6;185(2):469-74 PMID: 2555193
  63. DNA replication origin and transcriptional enhancer in c-myc gene share the c-myc protein binding sequences.
    EMBO J. 1989 Dec 20;8(13):4273-9 PMID: 2686984
  64. Isolation and characterization of s-myc, a member of the rat myc gene family.
    Proc Natl Acad Sci U S A. 1989 Dec;86(23):9144-8 PMID: 2594755
  65. The c-myc-regulated gene mrl encodes plasminogen activator inhibitor 1.
    Mol Cell Biol. 1990 Mar;10(3):1265-9 PMID: 2406566
  66. In vivo degradation of a transcriptional regulator: the yeast alpha 2 repressor.
    Cell. 1990 May 18;61(4):697-708 PMID: 2111732
  67. A rapid and simple method for preparation of RNA from Saccharomyces cerevisiae.
    Nucleic Acids Res. 1990 May 25;18(10):3091-2 PMID: 2190191
  68. The pathogenesis of Burkitt's lymphoma.
    Adv Cancer Res. 1990;55:133-270 PMID: 2166998
  69. Domains of human c-myc protein required for autosuppression and cooperation with ras oncogenes are overlapping.
    Mol Cell Biol. 1990 Sep;10(9):4961-6 PMID: 2201910
  70. An amino-terminal c-myc domain required for neoplastic transformation activates transcription.
    Mol Cell Biol. 1990 Nov;10(11):5914-20 PMID: 2233723
  71. Sequence-specific DNA binding by the c-Myc protein.
    Science. 1990 Nov 23;250(4984):1149-51 PMID: 2251503
  72. Cyclin is degraded by the ubiquitin pathway.
    Nature. 1991 Jan 10;349(6305):132-8 PMID: 1846030
  73. Degradation of nuclear oncoproteins by the ubiquitin system in vitro.
    Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):139-43 PMID: 1846034
  74. New light on Myc and Myb. Part I. Myc.
    Genes Dev. 1990 Dec;4(12A):2025-35 PMID: 2269425
  75. The MYC protein activates transcription of the alpha-prothymosin gene.
    EMBO J. 1991 Jan;10(1):133-41 PMID: 1989881
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.18.10.5961
Email
elizabeth.flinn@cbt.ki.se
Published
1998-10-00
Pages
5961-9
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC109182
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.18.10.5961 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: product@genelibs.com

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