L6 - Oncogenes and Tumour Suppressors II Flashcards
Is Abl encoded by an oncogene?
No, it is encoded by a proto-oncogene
BCR-Abl is encoded by an oncogene
General cancer pathway
Essentially, (TL;DR:) BCR-Abl is activated and stays constitutively active, resulting in various cancer-promoting pathways being constitutively active
- BCR-ABL signalling mimics growth factor activation.
- Growth factors are known to activate receptor tyrosine kinases (RTKs), leading to the activation of the RAS and PI3K/AKT pathways - these pathways are commonly activated in human cancers
- Phosphorylation of tyrosine 177 within the BCR part of BCR-ABL leads similarly to activation of these pathways by interacting with the SH2 domain in GRB2
- GRB2 activates RAS by interacting with the Son of Sevenless (SOS), and it also activates PI3K by mediating the phosphorylation of GAB2
- Constitutive activation of PI3K leads to the conversion of phosphatidylinositol bisphosphate (PIP2) phosphatidylinositol triphosphate (PIP3)
- This can be inhibited by phosphatase and tensin homolog (PTEN), a phosphatase that is down-regulated in many cancers
- PIP3 provides a platform for the recruitment of the serine/threonine kinases AKT and 3-phosphoinositide-dependent protein kinase-1 (PDK1), leading to phosphorylation and activation of AKT
- Activated AKT phosphorylates many downstream targets that affect proliferation and survival, including the FOXO transcription factors and the proapoptotic protein BAD
- AKT-mediated phosphorylation of FOXO inhibits its nuclear entry and therefore suppresses its activity, leading to increased cell proliferation
- The proapoptotic activity of BAD is also suppressed after AKT-mediated phosphorylation
- Phosphorylation of BAD prevents it from binding to and inhibiting the function of antiapoptotic BCL-2 proteins that inhibit the proapoptotic proteins BAK and BAX
- AKT activation leads to down-regulation of the tumour suppressor p53 by increasing the levels of the negative regulator of p53, MDM2
- AKT also phosphorylates the serine/threonine kinase mTOR
- Activated mTOR promotes protein translation and inhibits autophagy.
- BCR-ABL also leads to the activation of the JAK/STAT pathway, which is frequently activated in myeloproliferative diseases
- JAK is a nonreceptor tyrosine kinase and is normally activated by growth factors
- BCR-ABL has been shown to induce IL-3 and G-CSF production that could lead to activation of this pathway
- Active JAK phosphorylates the transcription factor STAT5 and BCR-ABL has also been shown to directly phosphorylate STAT5, leading to increased proliferation
Examples of proteins that are labelled as proto-oncogenes
- Transcription factors
- Kinases
- Signalling molecules
- Cell death regulators
This is applicable to these types of molecules if they have the potential to become an oncogene after mutation - ie Abl is a proto-oncogene as it has the potential to become an oncogene if its SH3 domain is damaged (ie through v-Abl/BCR-Abl)
Tumour suppressor genes: what are they, what do they do
Genes that code for proteins that suppress tumours
Repair DNA, protect genome form becoming mutated and forming oncogenes
HER2: what is it, what type of cancer is it overexpressed in, and what are some treatments for it?
RTK oncogene
Breast cancer
Pertuzumab and trastuzumab - these reduce its activity and stops its constitutive activity
Differentiating oncogenes and TSGs
Oncogenes - usually arise from constitutive activation following a gain of function
TSGs may undergo a loss of function and result in cancer