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.