1. The protein products of tumor-suppressor genes often function in conserved signaling pathways with other tumor-suppressor gene and oncogene protein products. Tumor-suppressor proteins are indicated with striped symbols and oncogene proteins with filled symbols. A, The pRb tumor-suppressor pathway. The protein product of the RB1 gene, pRb, is regulated by phosphorylation. The hyperphosphorylated form of pRb is inactive and unable to bind to E2F and regulate transcription of E2F-target genes. The cyclin D1 (CYC D1) and cyclin-dependent kinase 4 (CDK4) proteins appear to have a critical role in regulating pRb phosphorylation. The p16 protein is a critical inhibitor of the activity of the CYC D1 and CDK4 complex. Inactivating mutations in the pRb or p16 tumor-suppressor proteins or activating mutations (e.g., gene amplification) of CYC D1 or CDK4 are present in the majority of cancers. B, The APC and E-cadherin tumor-suppressor pathways. The APC protein, in collaboration with glycogen synthase kinase 3β (GSK3β), has a critical role in regulating β-catein (β-CAT) protein stability in the cell. If APC is inactivated by mutation, or β-CAT is activated by mutation of its N-terminus, β-CAT levels cannot be appropriately regulated. β-CAT complexes with Tcf (T-cell factor) or Lef (lymphoid-enhancer factor) transcription factors, such as Tcf-4, and activates expression of Tcf-target genes (e.g., c-MYC). β-CAT also functions in E-cadherin (E-CAD) cell-cell adhesion, linking E-CAD to the cytoskeleton via its interaction with α-catenin (α-CAT). E-CAD functions as a tumor-suppressor gene, although it is not clear that the consequence of E-CAD inactivation is similar to that of APC inactivation; i.e., there are no data to demonstrate that E-CAD and APC function in a shared or common signaling pathway even though both proteins interact with β-CAT. C, The patched (PTCH) tumor-suppressor pathway. Germ line mutations in the PTCH gene are responsible for Gorlin syndrome and hereditary nevoid basal-cell cancer syndrome, in which affected individuals develop large numbers of basal-cell cancers, as well as medulloblastomas. The PTCH protein inhibits the activity of the smoothened (SMO) protein, and the sonic hedgehog (Shh) factor regulates PTCH activity. SMO functions to activate expression of the Gli transcription factor. Inactivating mutations in PTCH, or activating mutation in SMO or Gli, have been found in cancer, and are mutually exclusive. D, The p53 tumor-suppressor pathway. p53 functions as a transcription factor and regulates expression of a large number of target genes with roles in cell cycle control and apoptosis (e.g., p21, Bax). p53 protein stability is regulated by the MDM-2 protein, and MDM-2 protein stability is regulated by the p19Arf (also known as p14Arf) protein. Inactivating mutation in p53 are found in upwards of 50 percent of all human cancers. In some cancers, activating mutations in MDM-2 or inactivation of p19Arf appear to have the same net consequence as p53 inactivation. (Figure modified with permission from Fig. 2 of Haber DA, Fearon ER. The promise of cancer genetics. Lancet 351 (suppl II):1, 1998.)
Source: Tumor-Suppressor Genes, The Online Metabolic and Molecular Bases of Inherited Disease
Citation: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. The Online Metabolic and Molecular Bases of Inherited Disease; 2014 Available at: Accessed: December 20, 2017
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