title: Regulation of the G1/S phase of the cell cycle and alterations in the RB pathway in human lung cancer.
abstract: The retinoblastoma (RB)-Cyclin (CCN)D1-p16 cell cycle pathway has a crucial role in lung tumorigenesis. Impairment of the RB pathway has been shown to occur in almost all lung tumors. A deregulation at any level of this core RB pathway seems to make cells insensitive to the mitogenic signaling that is required for cell cycle progression. To date, almost all participants in this pathway have been shown to be altered to a various degree in lung tumors. Some of the alterations are mutually exclusive, including RB and p16INK4A . In small cell lung cancer, the RB tumor suppressor gene is inactivated in almost 90% of the tumors, whereas in non-small cell lung cancer, the cyclin-dependent kinase (CDK)4 inhibitor p16INK4A is inactivated in 40-60% of the tumors. Many mechanisms may be responsible for activating the RB-Cyclin D1 pathway, including activating (CDK4) and inactivating mutations (p16INK4A ), deletions (RB and p16INK4A ), amplifications (CCND1 and CDK4), silencing methylation (p16INK4A and RB), and hyper-phosphorylation (RB). As some of these alterations, such as p16INK4A methylation, can also be detected in bronchial lavage and serum, they could potentially serve as useful markers for the early detection of lung cancer. This review summarizes recent experiments describing the variable roles of key-player molecules of the RB pathway and different mechanisms by which the RB pathway can be altered in lung cancer.
authors.affiliation: Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf Martinistrasse 52, D-20246 Hamburg, Germany. h.wikman@uke.uni-hamburg.de
authors.forename: Harriet
authors.initials: H
authors.lastname: Wikman
authors.forename: Eeva
authors.initials: E
authors.lastname: Kettunen
mesh_terms: D000818:Animals; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016161:Genes, Retinoblastoma / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D016196:S Phase / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics*