The cell cycle is a succession of events that lead to the duplication of a mother cell into two daughter cells, each cell containing the information necessary to repeat the process. In dividing cells, DNA replication and mitosis alternate (Alberts et al. 1994), and to ensure that one event is completed before the other one starts, there exist gap phases during which the cell checks that it can continue. The cell cycle is therefore divided in four phases: G1 (gap between M and S phases), S (DNA replication), G2 (gap between S and M phases) and M (Mitosis). In quiescent cells, the cells are considered to be in G0 phase. When they receive external signals, such as growth factors, a series of activations push the cell from a G0 to a G1 state and enters the cell cycle. At each phase, a surveillance mechanism checks that the cell can proceed to the next phase. For example, in late G1, the cell verifies that it is big enough to enter into DNA replication, during G2, that DNA replication is finished and during mitosis, that the chromosomes are properly aligned on the metaphase plate. If a problem occurs, the cell stops in one phase, attempts to resolve the problem and if it is possible, moves on with the cycle.
The cell cycle is orchestrated by a family of proteins, the CDKs (cyclin-dependent kinases) composed of two subunits, a kinase and a cyclin partner. These complexes phosphorylate a certain number of proteins, either activating or inhibiting them. Among them, the retinoblastoma tumor suppressor protein, RB, plays a key regulator role in cell cycle entry. It sequesters a family of transcription factors, E2Fs, responsible for the transcription of many genes involved in cell cycle regulation, DNA replication and in the activation of the apoptotic pathway. RB functions as a brake in the cell cycle which is released when external signals trigger S phase entry. The main targets of the external signals are the G1 cyclin/CDK complexes. Once active, the complexes phosphorylate RB which can then free E2F (DeGregori 2004).
RB is the target of many viral oncoproteins. It is also involved in many cancers either through a mutation of RB gene, in both familial forms of cancers and sporadic ones, or as a result of a deregulation of the kinases that control its activity. RB loss of function was first identified in retinoblastoma and since, has been clearly determined to be involved in many types of cancers (osteosarcomas, small cell lung carcinomas, breast carcinomas and other types of cancers (Knudson 1971; Friend et al. 1986).
Because of its implication in so many, if not all, cancers, the study of RB regulation requires a special attention. This is why, based on the literature, we built a quasi-exhaustive pathway around RB to relate the regulation of the tumor suppressor protein.
One purpose of the construction of this diagram, once validated, is to provide a map of the RB pathway that can become not only a reference when studying different cancers and mutations but also a tool to analyze formally the pathway and anticipate its deregulations (Nevins 2001).
