Oncogenes and tumour suppressors 1

• What is the Philadelphia chromosome?

  • This is found in many patients with CML.
  • Translocation between breakpoint cluster region (BCR) on chromosome 22 and the ABL genes, which encode a tyrosine protein kinase, on chromosome 9.
  • Results in the formation of a fusion protein, with missing N terminal sequences of the ABL protein and a shorter SH3.
  • Produces constitutively active ABL protein, which leads to overactivation of the Ras signalling pathway and ultimately suppression of apoptosis.
• Describe the action of Gleevec

  This is an anti-cancer drug that binds to the ATP-binding site in the BCR-Abl complex and prevents phosphorylation of target molecules. This can act as a treatment for CML>
• Describe retinoblastoma and its genetic cause

  • Hereditary disease that leads to the formation of a malignant tumour in the developing retina in childhood
  • Caused by inherited null mutation in the Rb gene, which is a tumour suppressor. This is usually followed by a second mutation, which results in loss of both copies of Rb.
  • Rb regulates restriction point in the cell cycle and loss of Rb results in uncontrolled proliferation.
• Describe the function of pRB

  pRB sequesters E2F, to prevent transcription of certain genes. Then pRB is phosphorylated during the cell cycle, leading to release of E2F so that it can increase expression of certain genes and drive the progression of the cell cycle.
• Describe the action of p53 in healthy and cancerous cells

  • p53 is a tumour suppressor that protects against DNA damage by regulating majority of the cell cycle checkpoints.
  • P53 binds to the p53 response element within the core promoter of specific genes, leading to recruitment of RNA polymerase.
  • P53 is a tetramer and each subunit contains a DNA binding domain, which binds to the response element
  • 50% of human cancers switch off p53, allowing tumour cells to suppress apoptosis and accumulate mutations.
• Describe the structure of Abl and how this structure is different compared to c-Abl

  • Inactive Abl is held in a tight conformation, preventing it from phosphorylating target. Signals lead to phosphorylation of Abl, resulting in a conformational change which forms an unclamped state and exposes the activation segment and allows Abl to phosphorylate its target molecules.
  • BCR-Abl oncogene product lacks the N terminal region of the SH3 domain, so the protein is in a constitutively active state.
• Describe how Ber-Abl suppress apoptosis

  1. Growth factors bind to RTKs
  2. Stimulates phosphorylation of tyrosine 177 within the BCR-Abl
  3. BCR-Abl interacts with SH2 domain on GRB2, which activates Ras by interacting with SOS.
  4. Ras activates PI3K, which converts PIP2 to PIP3.
  5. PIP3 recruits AKT, which phosphorylates downstream targets, including specific transcription factors and pro-apoptotic proteins, such as Bad, to suppress apoptosis.