Cancer: Genetic and Molecular Mechanisms

Regulation of the Cell Cycle and Cancer

Proto-Oncogenes and Oncogenes

Proto-oncogenes are normal genes that code for proteins involved in cell growth and division. When mutated or abnormally expressed, they can become oncogenes, which contribute to uncontrolled cell proliferation and cancer.

• Definition: Proto-oncogenes are genes that normally help cells grow. When a proto-oncogene mutates (changes), it becomes an oncogene, which can cause cells to grow out of control and lead to cancer.

• Three ways a proto-oncogene can become an oncogene:

  1. Translocation or Transposition: The proto-oncogene is moved to a new locus under control of a new promoter, leading to increased expression.

  2. Gene Amplification: Multiple copies of the proto-oncogene are made, resulting in excess protein production.

  3. Point Mutation: A mutation within the proto-oncogene or its regulatory elements increases its activity or stability, producing a hyperactive or degradation-resistant protein.

• Example: The ras gene can become an oncogene through a point mutation that leads to a hyperactive Ras protein, promoting cell division even in the absence of growth signals.

Normal Roles of Proto-Oncogenes and Tumor Suppressor Genes

• Proto-oncogenes: Promote normal cell growth and division by encoding growth factors, receptors, and signaling molecules.

• Tumor suppressor genes: Inhibit cell division, repair DNA mistakes, or initiate apoptosis (programmed cell death) when necessary. They act as the "brakes" of the cell cycle.

• Example: The p53 gene encodes a protein that halts the cell cycle in response to DNA damage and can trigger apoptosis if the damage is irreparable.

Mutations Leading to Cancer

• ras Gene Mutation: A mutation in the ras gene can produce a Ras protein that is always active, continuously sending signals for cell division, even without external growth factors. This leads to uncontrolled cell proliferation.

• p53 Gene Mutation: The p53 gene is a crucial tumor suppressor. Mutation in p53 disables its ability to halt the cell cycle or initiate apoptosis, allowing cells with DNA damage to survive and divide, increasing cancer risk.

Multistep Model of Cancer Development

Cancer typically develops through a series of genetic changes that accumulate over time. This multistep process involves:

• Activation of oncogenes (from proto-oncogenes)

• Inactivation of tumor suppressor genes

• Additional mutations that affect DNA repair, cell adhesion, and other regulatory pathways

Each step confers a selective growth advantage, leading to the formation of a malignant tumor.

Viruses and Cancer

• Viral Oncogenes: Some viruses can insert their genetic material into host DNA, disrupting normal gene regulation.

• Mechanisms:

  • Insertional mutagenesis: Viral DNA integrates near proto-oncogenes, activating them.

  • Viral proteins may inactivate tumor suppressor proteins (e.g., HPV proteins inactivate p53 and Rb).

• Example: Human papillomavirus (HPV) infection is linked to cervical cancer due to its effects on tumor suppressor genes.

Additional info: The above content expands on the objectives by providing definitions, mechanisms, and examples relevant to the molecular basis of cancer, as covered in General Biology (Ch. 18: Regulation of Gene Expression).