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Myc

Myc. Overview of Myc. Mammalian oncogene Transcription factor Located in the nucleus of cell Expressed in a wide variety of cancers. Myc family proteins. C-Myc N-Myc L-Myc S-Myc and B-Myc are “second cousins”. Myc Gene Structure. Located on chromosome 8q24 Consists of three exons

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Myc

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  1. Myc

  2. Overview of Myc • Mammalian oncogene • Transcription factor • Located in the nucleus of cell • Expressed in a wide variety of cancers

  3. Myc family proteins • C-Myc • N-Myc • L-Myc • S-Myc and B-Myc are “second cousins”

  4. Myc Gene Structure • Located on chromosome 8q24 • Consists of three exons • Transcription initiated at one of three promoters • Exon 2 = 439 AA, 64kDa c-Myc protein • Alternate translation sites result in longer and shorter forms of protein, p67 Myc and MycS respectively

  5. Myc Protein Structure • N-Terminal transactivation domain • C-Terminal basic helix-loop-helix leucine zipper motif ->two alpha helices held together between leucine residues ->mediates dimerization with other HLH LZ protein

  6. 5’-CA[C/T]GTC-3’ • This is termed the E or Myc Box

  7. Myc dimerization • Strictly requires dimerization with Max • Max is small, conserved HLH LZ protein

  8. DNA-Bound Myc-Max Complexes • Activate transcription through the amino terminal 143 AA’s of c-myc, called the transcriptional activation domain (TAD) • This region also required for transcriptional repression, but mechanism is not understood

  9. Myc function in Normal Cells • Tightly regulated by external signals, such as growth factors and extracellular matrix contacts • Growth factors increase expression as immediate early response gene • Expression persists through cell cycle but becomes quiescent in daughter cells

  10. Normal Cell Functions

  11. Myc regulates cell mass Mutation of Drosophila myc genes results in mutant ribosomal protein genes Cells are not fewer but smaller in size Regulation of Metabolism

  12. Regulation of Metabolism • Deregulation of human Myc might lead to increased tumor glycolysis • Known as the Warburg Effect

  13. Regulation of Metabolism • Heterozygous mice exhibit smaller growth and shorter tail length

  14. Regulation of Cell Cycle • Removal of c-myc leads to cells with remarkably slowed population doubling times • Most studies focus on G1-S phase transition

  15. Regulation of Cell Cycle • Myc induces cyclin D1 and D2 and Cyclin E, CDK4, and cdc25A • lowers the amount or inhibits the function of p27 • Induces Cul1 which mediates degradation of p27

  16. Mice Knockouts • Retarded growth • Death 9.5-10.5 days after gestation • Lack primitive homatopoiesis

  17. Myc overexpression in Cancer • Chromosomal translocation • Burkitt’s Lymphoma

  18. Myc Overexpression in Cancer • Gene amplification • Over 200 copies of N-myc found in neuroblastoma • Over 50 copies of N-myc, L-myc, or c-Myc found in small cell lung cancer • Elevation of myc in human colon carcinoma

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