细胞周期信号转导通路

Progress in the eukaryotic cell cycle is driven by oscillations(振动) in the activities of CDKs

(Cyclin-Dependent Kinases). CDK activity is controlled by periodic synthesis（周期复合体）and degradation of positive regulatory subunits（调节亚基）, Cyclins, as well as by fluctuations in levels of negative regulators, by CKIs (CDK Inhibitors), and by reversible phosphorylation. The mammalian cell cycle consists of four discrete phases: S-phase, in which DNA is replicated; M-phase, in which the chromosomes are separated over two new nuclei in the process of mitosis. These two phases are separated by two so called “Gap” phases, G1 and G2, in which the cell prepares for the upcoming events of S and M, respectively (Ref.1). The different Cyclins, specific for the G1-, S-, or M-phases of the cell cycle, accumulate and activate CDKs at the appropriate times during the cell cycle and then are degraded, causing kinase inactivation. Levels of some CKIs, which specifically inhibit certain Cyclin/CDK complexes, also rise and fall at specific times during the cell cycle (Ref.2). A breakdown in the regulation of this cycle leads to uncontrolled growth and contribute to tumor formation. Defects in many of the molecules that regulate the cell cycle also lead to tumor progression. Key among these are p53, the CKIs (p15 (INK4B), p16 (INK4A), p18 (INK4C), p19 (INK4D), p21, p27 (KIP1)), and Rb (Retinoblastoma Susceptibility Protein), all of which act to keep the cell cycle from progressing until all repairs to damaged DNA have been completed.

In mammalian cells, different Cyclin-CDK complexes are involved in regulating different cell cycle transitions: Cyclin-D -CDK4/6 for G1 progression, Cyclin-E -CDK2 for the G1-S transition, Cyclin-A

-CDK2 for S-phase progression, and Cyclin-A/B-CDC2 for entry into M-phase. Apart from these

well-known roles in the cell cycle, several Cyclins and CDKs are involved in processes not directly related to the cell cycle. Cyclin-D binds and activates the estrogen receptor. (Ref.6). The Cyclin-H -CDK7 complex is a component of both the CDK-activating kinase and the basal transcription factor TFIIH and can phosphorylate CDKs. Other Cyclins and CDKs (Cyclin-C-CDK8, Cyclin-T-CDK9, and Cyclin-K) are also associated with RNA Polymerase-II and phosphorylate the carboxyl-terminal repeat domain.

Cyclin-G, a target of p53, recruits PP2A (Protein Phosphatase 2A) to dephosphorylate MDM2 (Mouse Double Minute 2) (Ref.3).

Cyclins associate with CDKs to regulate their activity and the progression of the cell cycle through specific checkpoints. Disruption of Cyclin action leads to either cell cycle arrest, or to uncontrolled cell cycle proliferation. Mitogenic signals that are received by cell surface receptors communicate to the nuclear cell cycle machinery to induce cell division through growth factor receptors that target Ras, which signals to a number of cytoplasmic signaling cascades such as PI3K (Phosphatidylinositiol–3 Kinase), Raf and Rho. These proteins connect to the nuclear cell cycle machinery to mediate exit from Go into G1 and S-phase of the cell cycle. Activation of Ras leads to transcriptional induction of Cyclin-D1 in early G1 through a Ras-responsive element in the Cyclin-D1 gene promoter. Cyclin-D associates with CDK4 and CDK6 to form active Cyclin-D/CDK4 (or -6) complexes. This complex is responsible for the first phosphorylation of tumor suppressor Rb in G1 (Ref.1). Subsequently, Cyclin-E is synthesized. When Cyclin-E is abundant it interacts with the cell cycle checkpoint kinase CDK2 and allow progression of the cell cycle from G1 to S-phase. One of the key targets of activated CDK2 complexed with Cyclin-E is Rb. When dephosphorylated in G1, Rb complexes with and blocks transcriptional activation by E2F transcription factors. But when CDK2/Cyclin-E phosphorylates Rb, it dissociates from E2F, allowing E2F to activate the transcription of genes required for S-phase. E2F activity consists of a heterodimeric complex of an E2F polypeptide and a DP1 protein (Ref.5). One of the genes activated by E2F is Cyclin-E itself, leading to a positive feedback cycle as Cyclin-E accumulates. In S-phase, Cyclin-A is made, which