21.2 Tumor suppressors and proto-oncogenes

Cancer cells grow unchecked due to changes in two types of genes: tumor suppressors and proto-oncogenes. Tumor suppressors normally put the brakes on cell growth, while proto-oncogenes can turn into oncogenes that step on the gas.

Mutations in these genes lead to uncontrolled cell division and survival. Key players like p53, BRCA, and RAS regulate the cell cycle, DNA repair, and growth signaling. Understanding how they work helps explain how cancer develops.

Tumor Suppressors and Proto-Oncogenes

Functions of tumor suppressor genes

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  Frontiers | The Interplay Between Tumor Suppressor p53 and Hypoxia Signaling Pathways in Cancer View original

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• Regulate cell growth and division by inhibiting cell cycle progression (G1 to S phase)
• Promote apoptosis when necessary to eliminate damaged or abnormal cells
• Maintain genomic stability by monitoring DNA damage and initiating repair mechanisms (p53)
• Act as "gatekeepers" to prevent uncontrolled cell proliferation and tumor formation
• Examples of tumor suppressor genes include p53, BRCA1, BRCA2, APC, and RB1

Mutations in cancer development

• Loss-of-function mutations in tumor suppressor genes result in reduced or absent tumor suppressor activity
  • Leads to uncontrolled cell growth and division due to lack of cell cycle regulation
  • Allows cells to evade apoptosis and accumulate DNA damage without proper repair
• Gain-of-function mutations convert proto-oncogenes into oncogenes
  • Oncogenes exhibit constitutive activation or overexpression of growth-promoting proteins
  • Promotes excessive cell growth, proliferation, and survival even in the absence of normal growth signals
• Accumulation of mutations in both tumor suppressor genes and proto-oncogenes contributes to cancer development
  • Enables cells to acquire hallmark characteristics of cancer such as sustained proliferation, resistance to cell death, and genomic instability
  • Multiple mutations are typically required for full malignant transformation (two-hit hypothesis)

Examples of cancer-related genes

• p53: Mutated in various cancers including lung, breast, and colorectal cancer
  • Known as the "guardian of the genome" due to its critical role in maintaining genomic stability
• BRCA1 and BRCA2: Associated with hereditary breast and ovarian cancer
  • Involved in DNA damage repair and maintenance of genomic integrity
• APC: Mutated in familial adenomatous polyposis (FAP) and sporadic colorectal cancer
  • Regulates the Wnt signaling pathway and controls cell adhesion and migration
• RAS: Mutated in pancreatic, lung, and colorectal cancer
  • Oncogene that transduces growth factor signals and promotes cell proliferation
• MYC: Amplified or overexpressed in various cancers including Burkitt's lymphoma and neuroblastoma
  • Transcription factor that activates genes involved in cell growth, proliferation, and metabolism

Mechanisms of cell growth regulation

1. p53 induces cell cycle arrest or apoptosis in response to DNA damage or cellular stress
   • Activates p21, which inhibits cyclin-dependent kinases (CDKs) and halts cell cycle progression
   • Initiates apoptosis by upregulating pro-apoptotic genes (Bax, PUMA) and downregulating anti-apoptotic genes (Bcl-2)
2. RB1 binds and inhibits E2F transcription factors, preventing cell cycle progression from G1 to S phase
   • Hypophosphorylated RB1 sequesters E2F, preventing transcription of genes required for S phase entry
   • Phosphorylation of RB1 by CDKs releases E2F, allowing cell cycle progression
3. PTEN dephosphorylates PIP3, antagonizing the PI3K/AKT signaling pathway and inhibiting cell growth and survival
   • Loss of PTEN leads to constitutive activation of AKT, promoting cell survival and proliferation
4. RAS transduces growth factor signals from receptor tyrosine kinases (RTKs) to downstream effectors
   • Activates RAF-MEK-ERK and PI3K-AKT pathways, promoting cell proliferation and survival
   • Oncogenic mutations in RAS result in constitutive activation of these pathways
5. MYC transcription factor activates genes involved in cell growth, proliferation, and metabolism
   • Binds to promoter regions of target genes and recruits transcriptional machinery
   • Overexpression of MYC leads to uncontrolled cell proliferation and tumorigenesis