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Figure 1.

Without cyclin, CDK is inactive. pRB binds to E2F, preventing it from activating gene transcription on the

Without cyclin, CDK is inactive. pRB binds to E2F, preventing it from activating gene transcription on the

When cyclin binds to CDK, it is activated, adding a phosphate to pRB. This changes pRB's shape, and frees E2F. E2F binds DNA, and gene transcription occurs.

oscillate. There are G: cyclins, S-phase cyclins, and G2/M cyclins, each of which interact differently with CDK subunits to regulate the various phases of the cell cycle. CDKs can also associate with inhibitory subunits called CDK inhibitors (CKIs). In response to signals that work against proliferation, such as growth factor deprivation, DNA damage, cell-cell contact inhibition and lack of cell adhesion, CKIs cause the cell cycle to halt.

By the end of 2001, many structurally related cyclins (A1, A2, B1, B2, B3, B4, B5, C, D1, D2, D3, E1, E2, F, G1, G2, H, I, L, and T) and nine CDKs (CDK1 to CDK9) were identified in mammalian cells. Complexes of cyclin D and CDK4, as well as complexes of cyclin D and CDK6, operate during the G: phase. Complexes of cyclin A and CDK2, as well as complexes of cyclin E and CDK2, act during the transition from the G: to the S phase. Complexes of cyclin A and CDK1, as well as cyclin B and CDK1, function during the transition from the G2 to the M phase.

Active complexes of cyclins and CDKs exert their biological effects by phosphorylating proteins. During the G: phase, a major target of cyclin/ CDK complexes is the retinoblastoma protein (pRb). pRb is a growth-suppressing protein whose activity is controlled by whether or not it is phos-phorylated.

When pRb is in the dephosphorylated form, during the G0 phase and early in the G1 phase, it is active. pRb exerts its growth-suppressing effects

DNA.

DNA.

When cyclin binds to CDK, it is activated, adding a phosphate to pRB. This changes pRB's shape, and frees E2F. E2F binds DNA, and gene transcription occurs.

k gene ™ transcription

by binding to many cellular proteins, including the transcription factors of the E2F family (Figure 1). E2F transcription factors regulate the expression of numerous genes that are expressed during Gx, or at the transition from the G: to the S phase, to initiate DNA replication.

pRb that is bound to an E2F transcription factor inhibits the transcription factor's activity. Following phosphorylation by cyclin/CDK complexes, pRb dissociates from E2F, allowing the transcription factor to bind DNA sequences and activate the expression of genes necessary for the cell to enter the S phase. Cyclin D1/CDK4 complexes phosphorylation of pRb during the middle of the G: phase. They allow for subsequent phosphory-lation of pRb by additional cyclin/CDK complexes that act later in the cell cycle.

Two families of CKIs have been identified, based on their amino acid sequence similarity and the specificity of their interactions with CDKs. One of the families of CKIs, the INK family, includes four proteins (p15, p16 p18 and p20). These CKIs exclusively bind complexes of cyclin D and CDK4, as well as complexes of cyclin D and CDK6, to block cells that are in the G: phase of the cell cycle. The other family of CKIs, the Cip/Kip family, consists of three proteins (p21, p27, and p57). These inhibitors bind to all complexes of cyclins and CDKs that function during the G: phase and during the transition from the G: to the S phase. They act preferentially, however, to block the activity of complexes containing CDK2.

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