PRINCIPLES OF TOXICOLOGY - Biology East Borneo

284 CHEMICAL CARCINOGENESISTABLE 13.7 Tumor Suppressor Genes in Human Cancer and Genetic DiseaseGene Consequence of loss Function of encoded proteinRb Retinoblastoma and osteosarcoma Binds and sequesters the transcription factorE2F to maintain cells in G0 of cell cyclep53 Li-Fraumeni syndrome inactivated in>50% of human cancersTranscription factor with multiple functions,including cell cycle progression, detection ofDNA damage, and apoptosisp16 Familial melanoma, pancreatic cancer Inhibits CDK4 to block cell cycle progressionWt1 Wilms’ tumor/nephroblastoma Transcription factor required for renaldevelopmentVHL Von Hippel–Lindau syndrome renal cellcarcinomaNegative regulation of hypoxia-induciblemRNAsNF1 Neurofibromatosis type 1 schwannoma andgliomaGTPase-activating protein (GAP), whichregulates signaling through rasNF2 Neurofibromatosis type 2 acoustic nervetumors and meningiomasConnects cell membrane proteins with thecytoskeletonBRCA1 Familial and sporadic breast and ovarian Secreted growth factorcancer, also prostate and colon cancersBRCA2 Breast cancer (female and male) also prostate Unknown functioncancerDCC Colon cancer Cell adhesion moleculeAPC Familial and sporadic adenomatous polyposiscolorectal tumorsInteracts with catenins, proteins involved insignaling pathway for tissue differentiationMMR Hereditary nonpolyposis colorectal cancer Mediates DNA mismatch repairgene (Rb) and the discovery that both copies of the gene are inactivated and/or deleted in retinoblastomatumors. It is now known that a large proportion of persons with retinoblastoma have inherited adefective copy of the Rb gene. Tumors develop when the second copy is inactivated prior to the terminaldifferentiation of the retinoblasts. Another group of retinoblastoma patients do not have a defectivecopy of the Rb gene. In this group, two somatic mutations have occurred sometime after conception.Individuals born with a mutated copy of Rb gene are also at a higher risk of developing other cancers,most notably osteosarcoma, later in life. A number of the known or putative tumor suppressor genesappear to be involved in a relatively small subset of tumors specific to certain tissue types. These includeWt-1 (Wilms’ tumor), NF-1 and NF-2 (neurofibromatosis types 1 and 2), APC (adenomatous polyposiscoli), and DCC (deleted in colon carcinoma). In contrast to these, the p53 tumor suppressor gene, isinactivated in more than 50 percent of all human tumors. The p53 protein is a remarkable protein thatis involved in diverse cell functions including the detection of DNA damage, the regulation of cellcycle progression, and the induction of apoptosis or programmed cell death. Rb and p53 will bediscussed briefly below as well as in the context of the cellular functions in which they are involved.The p53 gene and the protein it encodes has been called the “guardian of the genome” in recognitionof the critical role it plays in the life and death of cells. The p53 gene is considered to be the mostfrequently mutated gene in human tumors. Approximately 40 percent of breast cancers, 70 percent ofcolon cancers, and 100 percent of small cell lung cancers contain mutations in the p53 gene. The p53gene encodes a 53-kD nuclear phosoprotein that is active in regulating the transcription of a numberof genes relating to cell cycle progression and apoptosis. Levels of p53 are increased in response toseveral types of cell stress, including DNA damage, hypoxia, and decreases in the levels of nucleotidetriphosphates required for DNA replication. The p53 protein has been shown to have a direct role inthe detection of DNA damage by some chemical carcinogens and radiation. In the presence of DNAdamage p53 has the ability to slow cell cycle progression or bring the cycle to a halt until the damagecan be repaired. In the face irreparable damage p53 has been shown to initiate the events leading toapoptosis.