L6 - Oncogenes and Tumour Suppressors II

Question 1

Is Abl encoded by an oncogene?

Answer 1

No, it is encoded by a proto-oncogene

BCR-Abl is encoded by an oncogene

Question 2

General cancer pathway

Answer 2

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

Question 3

Examples of proteins that are labelled as proto-oncogenes

Answer 3

• 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)

Question 4

Tumour suppressor genes: what are they, what do they do

Answer 4

Genes that code for proteins that suppress tumours

Repair DNA, protect genome form becoming mutated and forming oncogenes

Question 5

HER2: what is it, what type of cancer is it overexpressed in, and what are some treatments for it?

Answer 5

RTK oncogene

Breast cancer

Pertuzumab and trastuzumab - these reduce its activity and stops its constitutive activity

Question 6

Differentiating oncogenes and TSGs

Answer 6

Oncogenes - usually arise from constitutive activation following a gain of function

TSGs may undergo a loss of function and result in cancer