p53 gene product. p53 mutations can function as a dominant negative, meaning that a mutated p53 protein can prevent the function of the natural protein produced from the non-mutated allele. Other tumor-suppressor genes that do not follow the two-hit rule are those that exhibit haploinsufficiency, including PTCH in medulloblastoma and NF1 in neurofibroma. Another example is p27, a cell-cycle inhibitor, that when one allele is mutated causes increased carcinogen susceptibility. Functions The proteins encoded by most tumor suppressor genes inhibit cell proliferation or survival. Inactivation of tumor suppressor genes therefore leads to tumor development by eliminating negative regulatory proteins. In most cases, tumor suppressor proteins inhibit the same cell regulatory pathways that are stimulated by the products of oncogenes. While tumor suppressor genes have the same main function, they have various mechanisms of action, that their transcribed products perform, which include the following: Intracellular proteins, that control gene expression of a specific stage of the cell cycle. If these genes are not expressed, the cell cycle does not continue, effectively inhibiting cell division. (e.g., pRB and p16) Receptors or signal transducers for secreted hormones or developmental signals that inhibit cell proliferation (e.g., transforming growth factor (TGF)-β and adenomatous polyposis coli (APC)). Checkpoint-control proteins that trigger cell cycle arrest in response to DNA damage or chromosomal defects (e.g., breast cancer type 1 susceptibility protein (BRCA1), p16, and p14). Proteins that induce apoptosis. If damage cannot be repaired, the cell initiates programmed cell death to remove the threat it poses to the organism as a whole. (e.g., p53). Cell adhesion. Some proteins involved in cell adhesion prevent tumor cells from dispersing, block loss of contact inhibition, and inhibit metastasis. These proteins are known as metastasis suppressors. (e.g., CADM1) Proteins involved in repairing mistakes in DNA. Caretaker genes encode proteins that function in repairing mutations in the genome, preventing cells from replicating with mutations. Furthermore, increased mutation rate from decreased DNA repair leads to increased inactivation of other tumor suppressors and activation of oncogenes. (e.g., p53 and DNA mismatch repair protein 2 (MSH2)). Certain genes can also act as tumor suppressors and oncogenes. Dubbed Proto-oncogenes with Tumor suppressor function, these genes act as “double agents” that both positively and negatively regulate transcription. (e.g., NOTCH receptors, TP53 and FAS). Epigenetic influences Expression of genes, including tumor suppressors, can be altered through biochemical alterations known as DNA methylation. Methylation is an example of epigenetic modifications,