Cancer Module 2: Critical Cancer Genes

Critical Cancer Genes

Growth Factor Receptor Super Family

  • Proto-oncogenes: Growth Factor Receptor Super Family are proto-oncogenes.

  • Receptor Tyrosine Kinases (RTKs): These receptors activate the kinase domain upon ligand binding of growth factors.

  • Pro-growth Signaling: Generally considered a pro-growth signaling pathway.

  • Mutation/Amplification: Often mutated or amplified in cancer.

Epidermal Growth Factor Receptor (EGFR)

  • Dimerization and Transphosphorylation: Ligand binding allows receptor dimerization and transphosphorylation.

  • MAPK Pathway: Kinase domain phosphorylates downstream target genes to stimulate the MAPK pathway.

  • Ligand-Independent Kinase Activity: Mutations in the kinase domain allow ligand-independent kinase activity.

  • Anti-Cancer Drugs: Many anti-cancer drugs are designed to block kinase activity in mutant receptors.

Mechanisms of RTK Oncogenic Activation

  • Gene amplification and RTK domain mutations are common in many cancers.

    • Gene Amplification: Examples include HER2 in breast cancer and EGFR in colorectal cancer.

    • Point Mutations/Deletions: Seen in NSCLC (Non-Small Cell Lung Cancer).

Ras Signaling

  • Mediates RTK Signaling: Ras mediates signaling of RTKs.

  • Driver Mutations: Specific Ras driver mutations:

    • KRas: Lung, colon, and pancreas cancers

    • NRas: Melanoma

    • HRas: Bladder cancer

  • GTPase Mutations: Mutations of the Ras GTPase enable signaling independently of ligand signaling.

Mitogen Activated Protein Kinase (MAPK) Signaling

  • BRAF Driver Mutations: Found in colon, melanoma, thyroid, and ovarian cancers.

  • Erk Activation: Activated Erk translocates to the nucleus and activates DNA transcription factors.

  • GTP-Ras Binding: GTP-Ras binds to the Ras-binding domain in Raf to activate.

PI3K/Akt Pathway

  • Akt: A key pro-survival protein effector of PI3K activity.

  • PTEN: Phosphatase, often deleted.

  • PI3K Mutation: PI3K may be mutated.

  • Phosphorylation: PI3K phosphorylates PI(4,5)P2.

Wnt/APC/Beta-Catenin Pathway

  • Beta-Catenin: A multi-functional protein.

  • Destruction Complex: In the absence of Wnt ligands, beta-catenin is held in a destruction complex for proteosomal degradation, involving the APC gene.

  • Wnt Signaling: In the presence of Wnt, active signaling releases beta-catenin, which translocates to the nucleus to promote transcription of pro-growth target genes.

  • APC Gene: A tumor suppressor gene; mutations causing loss of function allow beta-catenin signaling.

p53 Tumor Suppressor

  • Master Regulator: The master regulator and stress sensor.

  • Mutation Frequency: Mutated in 50% of all cancers (most frequent).

  • Normal Cells: p53 is rapidly degraded in normal cells.

  • Stress Induction: Induced (stabilized) when a cell is stressed by DNA damage, telomere shortening, hypoxia, oxidative stress, or over-activation of signaling activities.

  • Cellular Response: Under stress, p53:

    • Halts the cell cycle for repair or condition change.

    • Induces apoptosis to prevent proliferation of damaged cells.

  • Cancer Inactivation: In cancer, p53 becomes inactivated through mutations, preventing its DNA-binding function and allowing damaged cells to proliferate.

p53 Regulation

  • p21 Expression: p53 stabilization regulates p21 expression, which controls Cdk, preventing cell cycle progression.

  • Mdm2: An E3 ubiquitin ligase targeting p53 for proteosomal destruction in normal conditions.

  • Cell Cycle Halt: Cell cycle is halted to allow repair.

  • Rb Phosphorylation: Rb becomes hypo-phosphorylated, preventing transcription of E2F promoter sites in cell growth genes.

Rb Tumor Suppressor

  • Rb is a TSG in the hypo-phosphorylated state.

  • p53 is a key regulator of Rb phosphorylation status through p21 CDK inhibitor

p53 Induced Apoptosis

  • p53 can induce many responses, including apoptosis (Programmed Cell Death).

p53 Mutations

  • Numerous and localized to the DNA binding domain.

Summary

  • Receptor Tyrosine Kinases (RTKs): Proto-oncogenes where mutations most often occur in the kinase domain.

  • Ras: A GTPase that regulates MAPK signaling and is often mutated, resulting in sustained proliferative signaling.

  • p53: The guardian of the cell that senses stress and halts the cell cycle or induces apoptosis. p53 is a TSG, widely mutated in its DNA binding domain in many cancers.