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c-Myc A Biological Paradox

c-Myc A Biological Paradox. Ashton Butler. Table of Contents. Introduction to c-Myc Normal role in the cell Relation to cancer Burkitt’s lymphoma. Introduction. Oncogene Found on Chromosome 8 Member of Myc protein family Includes N-myc and L-myc

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c-Myc A Biological Paradox

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  1. c-MycA Biological Paradox Ashton Butler

  2. Table of Contents • Introduction to c-Myc • Normal role in the cell • Relation to cancer • Burkitt’s lymphoma

  3. Introduction • Oncogene • Found on Chromosome 8 • Member of Myc protein family • Includes N-myc and L-myc • Basic helix-loop-helix leucine zipper (bHLH/LZ) transcription factors

  4. bHLH/LZ Transcription Factor Structure

  5. Normal Function • c-Myc activated through dimerization with Max • leads to transcription of target genes bHLH-LZ domain http://myc-cancer-gene.org/documents/MycReview.pdf E-box

  6. bHLH/LZ Transcription Factor Structure • Mad-max dimer represses transcription bHLH-LZ domain

  7. Normal Roles • Myc has 600+ identified gene targets • www.myc-cancer-gene.org • Main functions: • Cell proliferation • Apoptosis Hanahan and Weinberg, Cell 100:57-70 (2000)

  8. Determining Normal Roles: Mouse Models • Homozygous null mutant mice • lethal between 9.5 and 10.5 days of gestation • indicates role in cell proliferation • Over-expressed mutant mice • lethal 10 days-8 weeks after birth • indicates role in apoptosis http://biology.plosjournals.org/perlserv/?request=getdocument&doi=10.1371%2Fjournal.pbio.0020332

  9. Function: Cell Proliferation • Stimulates G1-S transition c-Myc low c-Myc high Growth Factors act at the Restriction Point

  10. Function: Regulation of Apoptosis • Over-expression in normal cells sensitizes the cell to a variety of apoptotic triggers

  11. Function: A Paradox • Ability to induce proliferation while at the same time being able to sensitize a cell to apoptosis is a “fail-safe” mechanism

  12. c-Myc and Cancer: back to the mouse model • Double mutant adult mice • tumorigenesis • Insertion of c-myc near various genetic enhancers • tumorigenesis in a variety of tissues • http://biology.plosjournals.org/perlserv/?request=getdocument&doi=10.1371%2Fjournal.pbio.0020332

  13. c-Myc and Cancer • Model: Unregulated c-Myc creates genetic instability G1-S checkpoint

  14. c-Myc and Cancer • Over-expressed in 70% of all human cancers • Translocated in 90% of all Burkitt’s lymphoma cases • 90% of gynecological cancers • 80% of breast cancers • 70% of colon cancers • Contributes to more than 70,000 cancer deaths annually in the U.S.

  15. c-Myc and Cancer: Burkitt’s Lymphoma • c-Myc was first discovered in lymphoma patients • Reciprocal translocation from chromosome 8 to chromosome 14 http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/B/BurkittLymphoma.html http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.92

  16. c-Myc and Cancer: Burkitt’s Lymphoma • Rare but extremely aggressive cancer • Predominantly affects children in Southern Africa • Solid tumor of B lymphocytes • High tendency to spread to CNS, bone marrow, other blood elements http://www.brown.edu/Courses/Digital_Path/systemic_path/female/burkitt.html http://tmcr.usuhs.mil/tmcr/chapter41/clinical.htm

  17. Summary of c-Myc • Transcription factor • Paradox: Functions in cell proliferation and apoptosis • Mouse model • Knockout: lethal (lack of cell proliferation) • Over-expressed: lethal (apoptosis) • Oncogene • Cancer: over-expression coupled with other mutations (i.e. tumor suppressors) leads to tumorigenesis in a variety of tissues

  18. References Cited • Beer S, Zetterberg A, Ihrie RA, et al:Developmental Context Determines Latency of MYC-Induced Tumorigenesis. PLoS Biology 2004, 2(11):e332. • Burkitt lymphoma. Genes and Disease. http://www.ncbi.nlm.nih.gov/books/bv .fcgi?call=bv.View..ShowSection&rid=gnd.section.92 • Burkitt’s lymphoma. 27 Aug. 2004. http://users.rcn.com/jkimball.ma.ultranet/ Biology Pages/B/BurkittLymphoma.html • Cosel H: Scientists discover role for c-myc gene in tumor angiogenesis. Innovations Report1 Jan. 2002. http://www.innovations-report.com/ specials/ printa.php?id=13299. • Gardner L, Lee L, Dang C:The c-Myc Oncogenic Transcription factor. http://myc-cancer-gene.org/documents/ MycReview.pdf • Pelengaris S, Rudolph B, Littlewood T: Action of Myc in vivo- proliferation and apoptosis. Current Opinion in Genetics and Development 2000, 10:100-105. • Nilsson JA, Cleveland JL: Myc pathways provoking cell suicide and cancer. Oncogene 2003, 22:9007-9021. • Weinberg, R: The Biology of Cancer. 2007. • Werner L, Leon J, Eilers M: Contributions of Myc to tumorigenesis. Biochimica et Biophysica Acta 2001, 1602:61-71. • Wyce M: Myc activates metastasis gene.Medical News Today 14 Sept. 2005. http://www.medicalnewstoday.com/medicalnews. php?newsid=30583.

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