MYCN Oncoprotein Flashcards
Describe how MYCN is broken down
Ser62 phosphorylatin by ERK or CDK1/CyclinB
Tyr58 phosphorylation by GSK3B
PP2A removes Ser62 phosphorylation
Ubiquitination by FBXW7
How does MYCN activate and repress genes
Activate: Binds to E boxes with max as a heterodimer
Repress: Binds with transcriptional repressors Miz and SP-1
What is the E box sequence
CACGTG
What genes does MYCN upregulate
ALK –> tyrosine kinase, promotes proliferation, migration and invasion
TERT -> lengthens telomeres
What genes does MYCN Repress
Clu –> inhibitor of metastasis and invasion
NGFR –> neurotrophin receptor which promotes neuronal differentiation and represses growth
What mutant protein does MYCN co-operate with and how
ALK –> mutant ALK prevents the T58 phosphorylation of mycn hence stabilises it
What micro RNA does mycn regulate
Upregulates miR17-92 –> these microRNAs target steroid hormone receptor, heterdimer nuclear receptors and orphan nuclear receptors which normally drive neuronal differentiation
ALso upregulate LIN28B
What proteins can we target in synthetic lethality in mycn
1) CDK2
2) Aurora Kinase A
3) PRMT5
What inhibits CDK2
Roscovitine
Why does inhibiting Aurora Kinase A help
Aurora Kinase A inhibits FXBW7 funciton hence inhibiting it allows it to degrade mycn
Why does inhibiting PRMT5 work
PRMT5 normally methylates MYCN and stabilises it
Methods of targeting MYCN
1) Targeting Mycn DNA binding
2) Target myc transcription
3) Target synthetic lethal interaction
4) Target onocgenic myc stabilisers
5) Target mycn expression
How can you target Mycn dna binding
pRevent Myc max interactin i.e. oncomyc shows potentiaon
HOw can we target myc transcription
Use BRD Inhibitors e.g. Oncoethix. Normallr BRD proteins copoerate with Bet proteins which cause an open chromatin structure at the myc proteins
How can we target synthetic lethal interactions of myc
Ihibits Auror A and CDK2
