Key Concepts of Section 24.5

• Overexpression of the proto-oncogene encoding cyclin D1 or loss of the tumor-suppressor genes encoding p16 and RB can cause inappropriate, unregulated passage through the restriction point. Such abnormalities are seen in 80 percent of human tumors.

• The INK4-ARF locus represents the most frequently mutated tumor-suppressor locus in humans, controlling both the RB and p53 pathways.

• The p53 protein is a multifunctional tumor suppressor that promotes arrest in G₁ and DNA repair or apoptosis in response to damaged DNA.

• Loss-of-function mutations in the p53 gene occur in more than 50 percent of human cancers. Overproduction of MDM2, a protein that normally inhibits the activity of p53, or inactivation of p14ARF, which also increases MDM2 activity, occur in several cancers that express normal p53 protein. Thus, in one way or another, the p53 stress-response pathway is inactivated to allow tumor growth.

• Human papillomavirus (HPV) encodes two oncogenic proteins: E6, which inhibits p53, and E7, which inhibits RB.

• Genome maintenance genes encode enzymes that repair DNA, or otherwise maintain the integrity of the chromosomes when DNA damage does occur. Mutations in genome maintenance genes lead to a high rate of mutagenesis of the genome that can lead to uncontrolled cell proliferation and accumulation of additional mutations, resulting in progression to metastatic cancer.

• Inherited defects in DNA-repair processes found in certain human diseases are associated with an increased susceptibility for certain cancers.