myc
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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 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
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
5’-CA[C/T]GTC-3’ This is termed the E
or Myc Box
Myc dimerization
Strictly requires dimerization with Max
Max is small, conserved HLH LZ protein
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
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
Normal Cell Functions
Regulation of Metabolism
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
Deregulation of human Myc might lead to increased tumor glycolysis
Known as the Warburg Effect
Regulation of Metabolism
Heterozygous mice exhibit smaller growth and shorter tail length
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
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
Mice Knockouts
Retarded growth Death 9.5-10.5 days after gestation Lack primitive homatopoiesis
Myc overexpression in Cancer
Chromosomal translocation
Burkitt’s Lymphoma
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