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

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

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?

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: http://images.google.com/imgres?imgurl=http://mcb.asm.org/content/vol19/issue1/images/large/mb0191642002.jpeg&imgrefurl=http://www.gmu.edu/departments/mmb/baranova/pages/ppt/LEX%2520X%2520-%2520Apoptosis.ppt&usg=__4C0mv387sSQzfC075KBeTUDhT6s=&h=888&w=1280&sz=200&hl=en&start=10&tbnid=_Oy8nfrwvwIEgM:&tbnh=104&tbnw=150&prev=/images%3Fq%3Dc-myc%2Bcrystal%26gbv%3D2%26hl%3Den%26sa%3DG Bottom: http://images.google.com/imgres?imgurl=http://www.ionchannels.org/pdb-image/1XAV.jpg&imgrefurl=http://www.cellcycles.org/structure.php%3Fstart%3D80&usg=__CW9UeQj9o9VKnDXjd3TDI2w_tLo=&h=250&w=250&sz=10&hl=en&start=34&tbnid=l7yLAzjPtDeRRM:&tbnh=111&tbnw=111&prev=/images%3Fq%3Dc-myc%2Bcrystal%26gbv%3D2%26ndsp%3D20%26hl%3Den%26sa%3DN%26start%3D20

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

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

The Role of c-myc in Cancer

How C-Myc Turns Oncogenic Paulsson et al. Leukemia 2003 Mutation Amplifications Insertional Mutagenesis Chromosomal Translocation Left: http://images.google.com/imgres?imgurl=http://www.sgul.ac.uk/depts/histopathology/bl8dn.GIF&imgrefurl=http://www.sgul.ac.uk/depts/histopathology/TumourProgression-1.html&usg=__csFmtKm17WjNBdvS31HNeiJUFX4=&h=445&w=662&sz=45&hl=en&start=3&tbnid=oURvj1PHpT45MM:&tbnh=93&tbnw=138&prev=/images%3Fq%3Dc-myc%2Bchromosomal%2Btranslocation%26gbv%3D2%26hl%3Den%26sa%3DG

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. 2000 Bottom: http://images.google.com/imgres?imgurl=http://www.bloodjournal.org/content/vol104/issue10/images/medium/zh80220469430004.gif&imgrefurl=http://www.canceruptodate.blogspot.com/&usg=__6jt6YIgvv9H7zssDev-OC5ZOOAI=&h=260&w=440&sz=22&hl=en&start=13&tbnid=UUQj-STzvVXqGM:&tbnh=75&tbnw=127&prev=/images%3Fq%3Dc-myc%2Bcell%2Bcycle%26gbv%3D2%26hl%3Den%26sa%3DG

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

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

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