myc and max interactions
TRANSCRIPT
M Y C ’ S S E C R E T L I F E W I T H O U T M A X
L U C A S C L A U D I O F E R N Á N D E Z L A L A N N E
MSc in Advanced Genetics
“ A S T O R Y O F I N F I D E L I T Y B E T W E E N T W O O N C O P R O T E I N S ”
A I M O F T H E P R E S E N TAT I O N
• Fully understand the implication of MYC and MAX proteins in normal cell processes
• Examine the implication of MYC-MAX dimers in cancer
• Study the function of the MAX gene in cancer
• Explain the possibility of MYC’s function without MAX
M Y C• Regulator gene that codes for a
transcription factor (15% of all genes)
• MYC protein plays a role in cell cycle, apoptosis and cellular transformation
• Mutations in MYC
• Leads to unregulated expression of genes involved in cell proliferation Discovered in Burkitt's lymphoma
• Cancer
c-MYC on chromosome 8
P R O M I S I N G TA R G E T F O R A N T I - C A N C E R D R U G S
• Increase its expression
M Y C A N D C A N C E R• Most of human tumors have high levels of MYC
• Increased levels of MYC are caused by gene amplification and translocation
• MYC deregulation has a great impact on cancer
MYC regulatory network in breast cancer
M A X
• MYC-associated factor X
• Regulator gene that codes for a transcription factor
• Forms dimers with MYC and other proteins
• Dimers compete for common DNA target sites
• Provides a complex system of transcriptional regulation
• MYC/MAX dimers promote cell proliferation and apoptosis
MAX on chromosome 14
MYC-MAX dimers targeting DNA
M A X A N D C A N C E R
• Caused by mutations that inactivate MAX
• These mutations seen in:
• Hereditary pheochromocytoma (PCC)
• Small cell lung cancer (SCLC)
• MAX alterations due tointragenic deletions
• Reason: MAX acts as a tumor suppressor gene and its inactivation causes cancer
S C L C
P C C
M A X A N D C A N C E R
M A X I S P R E F E R E N T I A L LY M U TAT E D I N N E U R O E N D O C R I N E - R E L AT E D M A L I G N A N C I E S
Inactivation of MAX found in SCLC (20% of LC) and not in NSCLC (80% of LC)
SCLC and PCC have neuroendocrine features
W H Y D O M Y C & M A X F O R M D I M E R S ?
MYC’s Leucine Zipper Domain
C O N T R O L O F T R A N S C R I P T I O N
B I N D I N G R E G U L AT O R Y
S E Q U E N C E S T O S P E C I F I C TA R G E T
G E N E S
MYC’s function? How?
C - E N D
R E C R U I T I O N O F T R A N S C R I P T I O N A L
C O - FA C T O R S T O A C T I VAT E O R R E P R E S S T H E E X P R E S S I O N
N - E N D
ZD binds DNA as protein:protein
dimers
M Y C C A N ’ T H O M O D I M E R I Z E
I N T E R A C T I O N W I T H M A X
( H E T E R O D I M E R )
P H E O C H R O M O C Y T O M A L I N E P C 1 2
Mutation which reppressed MAX protein synthesis
Forced expression of MYC induced apoptosis
and differentiation
M AY B E M Y C H A S A N A LT E R N AT I V E D N A - B I N D I N G PA R T N E R ?
c-Jun
I S M A X A N E S S E N T I A L PA R T N E R F O R M Y C ?
M Y C
M Y C
M A X
M A X
M Y C
O M O M Y C
O M O M Y C
Mutant version of MYC
Induction of apoptosisInduction of apoptosis
I S M A X A N E S S E N T I A L PA R T N E R F O R M Y C ?
M A X P R E S E N T M A X R E M O V E D
• Novel MYC activity proved in vitro - but, no in vivo evidence…
• Fortunately, MAX network is well conserved in Drosophila melanogaster
M A X - I N D E P E N D A N T M A X - D E P E N D A N T
T H E P I V O TA L R O L E O F M A X I N T H E M Y C / M A X N E T W O R K I S R E L AT E D M O R E T O R E P R E S S I O N T H A N T O A C T I VAT I O N
I S M A X A N E S S E N T I A L PA R T N E R F O R M Y C ?
C O N C L U S I O N S
• MYC is a major regulator of animal growth and development
• MYC is also an oncoprotein that has a big impact on human health
• It was thought that MYC’s function depended on MAX, but we have seen, both in vitro and in vivo, that MYC can function without MAX
• Biomedical aproach: Finding drugs that block MYC activity can be solved by interfering with the dimerization with MAX
R E F E R E N C E S• Burnichon, N., Cascón, A., Schiavi, F., Morales, N.P., Comino-Méndez, I., Abermil, N., Inglada-Pérez, L., Cubas, A.A. de, Amar, L.,
Barontini, M., et al. (2012). MAX Mutations Cause Hereditary and Sporadic Pheochromocytoma and Paraganglioma. Clin Cancer Res 18, 2828–2837.
• Cascón, A., and Robledo, M. (2012). MAX and MYC: A Heritable Breakup. Cancer Res 72, 3119–3124.
• Comino-Méndez, I., Gracia-Aznárez, F.J., Schiavi, F., Landa, I., Leandro-García, L.J., Letón, R., Honrado, E., Ramos-Medina, R., Caronia, D., Pita, G., et al. (2011). Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 43, 663–667.
• Crona, J., Maharjan, R., Verdugo, A.D., Stålberg, P., Granberg, D., Hellman, P., and Björklund, P. (2013). MAX mutations status in Swedish patients with pheochromocytoma and paraganglioma tumours. Familial Cancer 13, 121–125.
• Dang, C.V. (2012). MYC on the Path to Cancer. Cell 149, 22–35.
• Donaldson, T.D., and Duronio, R.J. (2004). Cancer Cell Biology: Myc Wins the Competition. Current Biology 14, R425–R427.
• Hurlin, P.J., and Dezfouli, S. (2004). Functions of Myc:Max in the Control of Cell Proliferation and Tumorigenesis. B.-I.R. of Cytology, ed. (Academic Press), pp. 183–226.
• Peter Gallant, D.S. (2009). Myc’s secret life without Max. Cell Cycle (Georgetown, Tex.) 8, 3848–3853.
• Romero, O.A., Torres-Diz, M., Pros, E., Savola, S., Gomez, A., Moran, S., Saez, C., Iwakawa, R., Villanueva, A., Montuenga, L.M., et al. (2014). MAX Inactivation in Small Cell Lung Cancer Disrupts MYC–SWI/SNF Programs and Is Synthetic Lethal with BRG1. Cancer Discovery 4, 292–303.
• Soucek, L., Whitfield, J., Martins, C.P., Finch, A.J., Murphy, D.J., Sodir, N.M., Karnezis, A.N., Swigart, L.B., Nasi, S., and Evan, G.I. (2008). Modelling Myc inhibition as a cancer therapy. Nature 455, 679–683.
• Xu, J., Chen, Y., and Olopade, O.I. MYC and Breast Cancer.
• (1999). The Myc oncoprotein: a critical evaluation of transactivation and target gene regulation. , Published Online: 13 May 1999; | doi:10.1038/sj.onc.1202748 18.