1. The Role of Myc A Master Regulator Gone Awry
Novus Biologicals
The Role of Myc
Rummukainen et al. Mod pathol 2001
Top Left: Detection of c-myc Tagged Plakoglobin by Immunofluorescence. Samples are of Human microvascular endothelial cells expressing c-myc tagged plakoglobin following transient transfection
Top Right: Highly amplified c-myc Oncogene
A Master Regulator Gone Awry

2. How MYC was discovered
Pioneering work by Diana Sheiness and J. Michael Bishop from 1978 to 1979
First discovered that MC29, an avian carcinoma retrovirus does not contain the src gene(1978)
Further study of MC29 led to the discovery of the c-myc oncogene (1979)
Conserved among many species including Chicken, Cows, Mice, and Salmon
Later on, the Myc family proteins were discovered (c-Myc, N-Myc, L- Myc, and also S and B-Myc)
MC29V DNA
From Sheiness et al. 1978

3. Discovering The role of normal c-Myc
Highly Regulated Expression
High mRNA turnover
Early Immediate Response
Gene
Extremely short half-life
Responds quickly to extracellular cues
Highly Conserved among different species
So…What could c-Myc be?

4. C-Myc is a Transcription Factor
Structural Elements
Leucine Zipper Domain
Helix-loop-helix Domain
Max partner protein
CACGTG E-box
TRRAP (transactivation/
transformation association protein)
Top picture:
Bottom:

5. C-Myc: A Transcriptional Activator
Promotes RNA Polymerase II (Phosphorylation of C-terminus and mRNA cap)
Recruits RNA Polymerase through pTEFb
Histone Acetylation
Chromatin Remodeling With hSNF5 of the SWI-SNF complex
C-myc

6. C-Myc: A Transcriptional Repressor
Negative Feedback Loop
Autoregulation
Repress Promoter Activity
Myc-Max complexes interact with NFY, SP1 and MIZ1
C-myc represses as many if not more proteins as it activates

7. The Role of c-myc in Cancer

8. How C-Myc Turns Oncogenic
Paulsson et al. Leukemia 2003
Mutation
Amplifications
Insertional Mutagenesis
Chromosomal Translocation
Left:

9. Effects of Oncogenic C-Myc are Pervasive in most Cancers
Cell Cycle Deregulation
Genomic Instability
Angiogenesis
Negative effects in Cell Growth, Size, and Differentiation (Proliferation)
Langois et al
Bottom:

10. The Apoptotis Paradox???
Normal Cells – Overexpression of Myc triggers Apoptosis
Requires Max
Induces release of cytochrome C
Cyto C, APAF1, and Procaspase-9 form the Apoptosome
ATP causes Caspase cascade which causes degradation of cell components
Pelengaris et al, 2002

11. Knockout Mice Give Insights
Meyer et al. Nature Reviews Cancer 2008
Myc-null is embryonic lethal
Eµ-Myc mice (useful transgenic mouse model) show Clonal B-cell Lymphoma

12. The C-Myc Tree of Knowledge: How Myc has changed science
Meyer et al. Nature Reviews Cancer 2008
The C-Myc Tree of Knowledge: How Myc has changed science