c-myc Flashcards
What translocation occurs in Burkitts Lymphoma
t(8:14) –> puts the myc gene near the IgH gene promoter that is heavily expressed in B Cells
What 3 ways can activate c-myc in oncogenesis1
Proviral gene insertion
Amplification
Chromosomal Translocation
Describe the structure of the myc protein
439a.a 2 Myc boxes NLS Basic Domain LZ HLH
What does c-myc bind to
E-box sequences
CACGTG
What is heterochromatin
DNA is densely packed
What is euchromatin
DNA is loosely packed
What are the 2 ways that RNA PolII Can Get access to chromsomes
Histone modification
ATP - dependent chromsome modification
Describe ATP-dependend chromosome remodelling
Complex protein binds to the nucelosome
ATP is used to move the nucleosome out of the way
Causes loosening of the chromsome
ALlows remodellign through octamer sliding or octamer transfer
What is open complex formation
When the template strand of DNA is seperated to allow access
What is the CTD
THe CTD is a 52 a.a. repeat motif that is bound to the RNA Pol II and its phosphorylation state helps describe the position of the polymerase
Describe the different phosphorylations that occur to RNA Pol II as it moves
Pre-Initiation - No Phosphorylation
Initiation: Ser5 Phosphorylation by TFIIH
Elongation: Phosphorylation at Ser2 by PTEFb
Termination: Removal of Ser5 phosphorylation by Ser5 phosphatase
What is Chip-Seq
Use formaldehyde to cross link bound protein to DNA
Isolate chromatin and shear the DNA
Precipirate chromatin with specific Ab
Reverse cross link and digest proteins
Construct a fradment library to allow it to undergo high density sequencing
What causes the proximal promoter pausing
NELF and DSIF
What releases promoter proximal pausing
PTEFb –> causes DSIF to be phosphorylated most important step as causes pause release
NELF Also disssociates from the complex but DSIF stays with it
THe whole process if important and is hence why myc is involved in transctiptional regulation
What dimerizes with myc
Max
What else can max bind with
Mad
Myc max causes whet
Transcriptional acitvation
Mycmad causes what
Transcriptional repression
How does myc max wor
Binds to E box
Recruits TRRAP –> recruits HATs.
Recruits PTEFb –> proximal pause release
Recruits SWI/SNF –> ATP dependent chromatin remodeller
How does mycmad work
Recruits the SIN3 adaptor protein
This recruits HDACs
How can myc max cause transcriptional repression
Prevents the interaction of Miz-1 and NPM1 by bidning to it hence prevents the transcriptional activity of Miz-1
What is the rate limiting step of transcription
The recruitiment of pTEFb hence myc helps overcome this
What do the other 2 RNA polymerases do
RNA Pol 1 - rRNA
RNA Pol II –> tRNA, 5srRNA, snRNA
How does myc regulate RNA Pol I
Binds to E boxes
How does myc regulate RNA Pol III
No E boxes hence interacts with TFIIIB and recruits HATs, specifically recruits GCNS, a specific HAT for RNA Pol III
What genes does myc activate
Protein biosynthesis
Metablistm
Transcription factors and cell cycle e.e. E2F
What genes does myc inhibit
CDKIs
Bcl-2
Cell Adhesion Molecules
Wnt Signalling Inhibitors
How does myc induce apopotosis
Upregulates ARF ( as produces E2F)
What form of myc causes differentiation
myc-nick
How does myc-nick cause differentiation
Myc-nick lacks the DNA binding domain
Instead regulates alpha-tubulin acetylation throguh same acetyltransferases as in the nucelas, GCN5 specifically
What are the four transcription factors involved in maintaining pluripotency in stem cells
C-myc
Oct4
Sox2
Klf4
how is mRNA of myc regulated
Translational independent - involves the polyA tail shortening regualted by AU-rich regions in the 3’ UTR
Translational depenednt - regulated by the coding region determinant
How does c-myc promote angiogenesis
Promotes the miR17-92 which downregulates thrombospandin - anigiogenesis
Why is myc hard to target
Lacks hydrophobic pocket
Unorganized tertiary structure and protein-protein interactions
How does EBV activate myc in Burkitts lymphoma
EBNA2 protein activates it
What B Cell lymphomas is myc activated in
Burkitts
DLBLCL
Mantle cell lymphome
CLL –> poor prognosis if myc translocatoins. Richeter synrome (transformed CLL - 26% had myc alteratoins
What T cell malignancies is myc activated in
Anaplastic large cell lymphoma
T-ALL
P-ALL
What myeloid malignancies is myc deregulated in
AML and CML
What gene fusion products can increase myc
RunXI-RUNXITI and PML-RARa
How can we ratget myc deregulation
Target myc-max interaction
Increaese myc degradation
Target myc expression throguh epigenetic deregulation
How can we target myc associated vulnerabiltiesL Cell cycle inhibiton, resstablish apopotosis, protein biosynthesis
What is the effect that we can exploit in cacner cells
The Wardburg effect which affects rapidly dividing cancer cells
What post translational protein modifications can occur in myc
Proteasome inhbitiro (Bartezomib) can cause ER stress in cancers with myc i.e. multiple myeloma
