GENES REGULATED BY C MYC

Summary

Principal Investigator: Emmett Schmidt
Abstract: DESCRIPTION: (Adapted from the investigator's abstract) Tumor-specific translocations and deregulated expression activate the oncogene c-myc in many cancers. Genetic models and target genes identify myc as an important element in growth control. The applicant identified translation initiation factor eIF4E as a critical target of c-Myc because co-transfection with a dominant inhibitor of eIF4E (4EBP1) blocks transformation by c-Myc and eIF4E itself transforms cells. To understand mechanisms coupling growth and cell division, the applicant evaluated the response of cell cycle genes to regulation by translation initiation factors. He found translational controls of CLN3 (a cyclin D1 homologue) that couple cell division to cell growth. eIF4E is a specific myc target because its promoter contains c-Myc binding sites adjacent to a novel element (CTCTTACCCCCCCTT) at -25 that is necessary for Myc-transactivation. Furthermore, levels of eIF4E regulatory factors (4ERFs) binding this element correlate with c-Myc and protein synthesis. Thus, c-myc specifically up-regulates translation factors, and translation factors specifically regulate genes controlling the cell cycle. His data suggest that regulation of eIF4E is a crucial step in myc-induced oncogenesis. Two aims will assess the significance of eIF4E in cell transformation by c-myc: (Aim 1) He will identify mechanisms by which expression of constitutively active, dominant inhibitors of eIF4E block transformation by c-myc. (Aim 2) He will evaluate growth control in c-myc -/- fibroblasts to identify the molecular basis for their defect in protein synthesis. Two aims will focus on myc-4ERF interactions: (Aim 3) Reporter assays will assess transcriptional functions of the -25 element (LS3). Manipulations of its position, orientation and copy number in heterologous constructs will assess its potential as an activator, repressor, initiator, or as a TATA substitute. Co-transfections with c-myc expression vectors and the eIF4E promoter constructs will test for synergism between the 4ERFs and c-Myc. (Aim 4) 4ERFs will be cloned using DNA-binding site probes and yeast one-hybrid systems. Their molecular weights and binding site suggest they will be novel factors. Full-length clones will be identified to use in expression constructs to evaluate synergism between c-myc and the 4ERFs. Biological functions of the 4ERFs in growth regulation will be analyzed and their potential regulation by c-myc tested.
Funding Period: 1994-06-01 - 2006-06-30
more information: NIH RePORT

Top Publications

  1. pmc Mammary tumorigenesis following transgenic expression of a dominant negative CHK2 mutant
    Eunice L Kwak
    Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA
    Cancer Res 66:1923-8. 2006
  2. ncbi Heat shock protein B8, a cyclin-dependent kinase-independent cyclin D1 target gene, contributes to its effects on radiation sensitivity
    Sally Trent
    Oxford Cancer Centre, Department of Radiotherapy, Churchill Hospital, Oxford, United Kingdom
    Cancer Res 67:10774-81. 2007
  3. pmc Growth controls connect: interactions between c-myc and the tuberous sclerosis complex-mTOR pathway
    Emmett V Schmidt
    Cancer Research Center at Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA
    Cell Cycle 8:1344-51. 2009
  4. pmc Genome-wide analysis of YY2 versus YY1 target genes
    Li Chen
    Cancer Research Center at Massachusetts General Hospital, Boston, MA 02114, USA
    Nucleic Acids Res 38:4011-26. 2010
  5. pmc hnRNP K binds a core polypyrimidine element in the eukaryotic translation initiation factor 4E (eIF4E) promoter, and its regulation of eIF4E contributes to neoplastic transformation
    Mary Lynch
    Cancer Research Center at Massachusetts General Hospital and Harvard Medical School, 55 Fruit St, Boston, MA 02114, USA
    Mol Cell Biol 25:6436-53. 2005
  6. pmc c-myc Repression of TSC2 contributes to control of translation initiation and Myc-induced transformation
    Michael J Ravitz
    Cancer Research Center at Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
    Cancer Res 67:11209-17. 2007

Scientific Experts

  • Emmett Schmidt
  • Li Chen
  • Mary Lynch
  • Michael J Ravitz
  • Chuanwei Yang
  • Sally Trent
  • Eunice L Kwak
  • Kathryn R Coser
  • Mary C Lynch
  • Toshi Shioda
  • Cuiqi Li
  • Jianmin Zhang
  • Robert D Cardiff
  • Sang Kim
  • Daniel A Haber
  • Sapna Mehtani
  • Kevin Korenblat
  • Michael J Pazin

Detail Information

Publications6

  1. pmc Mammary tumorigenesis following transgenic expression of a dominant negative CHK2 mutant
    Eunice L Kwak
    Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA
    Cancer Res 66:1923-8. 2006
    ..The increased rate of tumor formation in MMTV-CHK2-D347A mice, compared with the relatively low incidence in chk2-null mice, provides a model to study modifiers of CHK2-dependent transformation...
  2. ncbi Heat shock protein B8, a cyclin-dependent kinase-independent cyclin D1 target gene, contributes to its effects on radiation sensitivity
    Sally Trent
    Oxford Cancer Centre, Department of Radiotherapy, Churchill Hospital, Oxford, United Kingdom
    Cancer Res 67:10774-81. 2007
    ..Taken together, our results show that some of cyclin D1's effects on radiation sensitivity are CDK and p21 independent and identify HSPB8 as a candidate CDK-independent cyclin D1 target that can mediate its effects...
  3. pmc Growth controls connect: interactions between c-myc and the tuberous sclerosis complex-mTOR pathway
    Emmett V Schmidt
    Cancer Research Center at Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA
    Cell Cycle 8:1344-51. 2009
    ..Further experiments will be needed to clarify the mechanisms underlying this important connection, and evaluate its overall contribution to cancers caused by TSC loss or Myc gain...
  4. pmc Genome-wide analysis of YY2 versus YY1 target genes
    Li Chen
    Cancer Research Center at Massachusetts General Hospital, Boston, MA 02114, USA
    Nucleic Acids Res 38:4011-26. 2010
    ..Our studies show that human YY2 is not redundant to YY1, and YY2 is a significant regulator of genes previously identified as uniquely responding to YY1...
  5. pmc hnRNP K binds a core polypyrimidine element in the eukaryotic translation initiation factor 4E (eIF4E) promoter, and its regulation of eIF4E contributes to neoplastic transformation
    Mary Lynch
    Cancer Research Center at Massachusetts General Hospital and Harvard Medical School, 55 Fruit St, Boston, MA 02114, USA
    Mol Cell Biol 25:6436-53. 2005
    ..hnRNP K is an unusually diverse regulator of multiple steps in growth regulation because it also directly regulates c-myc transcription, mRNA export, splicing, and translation initiation...
  6. pmc c-myc Repression of TSC2 contributes to control of translation initiation and Myc-induced transformation
    Michael J Ravitz
    Cancer Research Center at Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
    Cancer Res 67:11209-17. 2007
    ..Together, these findings show that regulation of TSC2 can contribute to the effects of Myc on cell proliferation and neoplastic growth...