c-myc Flashcards by Jacob Lewis

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

How well did you know this?

Not at all

Perfectly

What 3 ways can activate c-myc in oncogenesis1

Proviral gene insertion
Amplification
Chromosomal Translocation

How well did you know this?

Not at all

Perfectly

Describe the structure of the myc protein

439a.a
2 Myc boxes
NLS
Basic Domain
LZ
HLH

How well did you know this?

Not at all

Perfectly

What does c-myc bind to

E-box sequences

CACGTG

How well did you know this?

Not at all

Perfectly

What is heterochromatin

DNA is densely packed

How well did you know this?

Not at all

Perfectly

What is euchromatin

DNA is loosely packed

How well did you know this?

Not at all

Perfectly

What are the 2 ways that RNA PolII Can Get access to chromsomes

Histone modification

ATP - dependent chromsome modification

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

What is open complex formation

When the template strand of DNA is seperated to allow access

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

What causes the proximal promoter pausing

NELF and DSIF

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

What dimerizes with myc

Max

How well did you know this?

Not at all

Perfectly

What else can max bind with

Mad

How well did you know this?

Not at all

Perfectly

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