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