Lecture 4: Sustained proliferative signaling II Flashcards
Particularity of cytokine receptors ?
Function like RTKs but they “outsourced” their TK domain to a family of interacting partners, the JAKs (Janus Kinases)
What is the effect of receptor phosphorylation by JAK?
It creates docking sites for STAT1 and STAT2
(Signal Transducer and Activator of Transcription)
What happens when JAK phosphorylates directly the STATs ?
They dimerize and are translocated in the nucleus (where they act as transcription factors)
Why inhibition of JAK is not clinically approved yet?
Because of high toxicity and unintended immune suppression of JAKinibs
MYC’s characteristics
-Yamanaka factors
-upregulated in most cancer
types, e.g. due to altered
growth factor signaling
-Promotes multiple cancer
hallmarks, incl. proliferation
What is the effect of blocking MYC expression in a mouse with hepatocellular carcinoma?
Blocking MYC causes tumor regression, showing its role in cancer growth
What is omomyc and how is it used?
-It’s a cell-penetrating miniprotein
-It’s used to block the binding of MYC to MAX (obligate partner)
-Omomyc transgene can eradicate cancer in multiple tissues (in mouse)
Examples of cell cycle genes stimulated by MYC
Cyclin D, Cyclin E, Cdk2, Cdk4,6
Definition of oncogenes
Genes that
promote cancer when
mutated or amplified
Definition of proto-oncogenes
Wildtype genes with the
potential to become oncogenic upon
upregulation, or upon gene amplification or mutation
Give the canonical Wnt/β-catenin signaling pathway (when it’s ON)
-Wnt binds to frizzled
-GSK-3β / APC complex is inactive
-β-catenin is stabilized and can translocate to the nucleus
-TCF target genes are ON
What happens when Wnt pathway is “OFF”
β-catenin is degraded by the complex of APC and kinases (GSK3β)
What is the consequences of mutation hotspots in APC structure?
It disrupts the β-catenin binding region
In 90% of sporadic colon carcinomas, APC is inactivated by…
… somatic mutation or hypermethylation
Are oncogenic mutations in β-catenin randomly distributed across the protein?
No, these mutations often affect phosphorylation sites that are normally targeted by GSK-3β for degradation
Give the type of alteration and examples of:
1) oncogenes
2) tumor suppressor genes
1) gain-of-function/ EGFR, RAS, β-catenin
2) loss-of-function/ APC, NF-1, PTEN (on les verra plus tard ;))
“FAP” signification and cause
Familial Adenomatous Polyposis (la photo dégueu du cours) caused by mutations in the APC
What are CBC stem cells and how are they regulated?
They are Crypt Base Columnar stem cells and are regulated (proliferation or quiescence state) by WNT and its antagonist: ‘secreted frizzled-related protein’ (sFRP)
What is LGR5 and what role does it play?
It’s a ‘Leucine-rich repeat containing G protein-coupled receptors’ and it increases the activity of the Wnt/Fz signaling pathway (positive feedback)
How does Cre/Lox technique work?
The LoxP sites inactivate the gene, but it remains in the genome.
The Cre recombinase is used to remove the gene at a specific time (temporal control) and/or in specific tissues (spatial control)
Why Lgr5+ CBC cells are tumor initiator?
They sustain the activation of β-catenin signaling⇒overexpression of the cMyc oncogene⇒cell proliferation
Give the three types of ubiquitination
1) Mono-Ub (substrate+ 1 Ub)
2) Multi-Ub (substrate + 2 Ubs)
3) Poly-Ub (substrate + >=4 Ubs )
Give the effects of Mono and Multi Ub
- change protein conformation
- trigger endocytosis of RTKs and other cell surface receptors to target lysosomes
- UBM-containing proteins can bind to the Ub-substrate and modify its fate
Give the effect of poly-Ub
Degradation by
26S proteasome.
For example, K48 polyubiquitin marks proteins for proteasomal degradation
