The kinetics of cell proliferation in tumours depends on the balance between the proliferation index and the rate of deletion, which in part occurs by apoptosis.
Transition through the cell cycle is controlled at various checkpoints. These are regulated by a family of serine/threonine protein kinases, consisting of regulatory cyclin subunits which activate cyclin-dependent kinases (CDKs). Eleven cyclins have been identified (A, B1, B2, C, D1, D2, D3, E, F, G & H).
p53 arrests cells in G1 in response to stress.
The late G1 checkpoint is controlled by cyclins D1, D2 and D3, along with CDK4 and CDK6. These form complexes which act upon proteins of the retinoblastoma gene family (pRb/p105, pRb2/p130 and p107. These proteins in turn interact with the E2F/DP family of transcription factors. Excessive expression of D1 causes early phosphorylation of the pRb proteins and acceleration of the cell cycle through G1.
Entry to the S phase and centromere duplication are dependent on cyclin E. This complexes with CDK2. Activation of the cyclin E gene is dependent on E2F and the destruction of cyclin E is mediated by ubiquitin. Cyclin A, again bound to CDK2, is also required for entry to the S phase; cyclin A takes over the activation of CDK2 from cyclin E during the S phase. The complex of Cyclin A, CDK2 and p107 initiates and maintains DNA synthesis, by activating proteins at the DNA replication sites. The completion of the S phase is accompanied by cyclin A complexing with CDK1 and p34(Cdc2). The term M2 phase promoting factor" (MPF) is applied to cdc2/p34 in complex with cyclin A or B.
During G2 the completeness and accuracy of DNA replication are ensured. Entry to mitosis is dependent on CDK1 p34. p53 prevents cells from entering mitosis if they have passed through the S phase with insufficient substrates to complete DNA synthesis or have entered G2 with damaged DNA: it does so by inhibiting CDK1.
The process of mitosis is dependent on the presence of the cyclin B1 - CDK1/p34 complex: cyclin B1 is absent during G0, G1 and the S phase, accumulating only during G2. Cyclin B1 is degraded at anaphase. Lack of cyclin B in Hodgkin's disease may account for the abortative mitoses seen in Reed-Sternberg cells.
Seven CDK inhibitors have been identified:
the INK4 family consists of INK4a (p16), INK4b (p15), IN4c (p18) and INK4d (p19). the INK4 proteins bind CDK4 and CDK6, preventing D-type cyclins form binding and activating these kinases. INK4a and INK4b are themselves regulated by the pRb family.
the CIP/KIP family consists of CIP1/WAF1 (p21), KIP1 (p27) and KIP2 (p57). All three bind and regulate multiple CDK-cyclin complexes. KIP1 may activate CDK4/6-cyclin D complexes, as well as inhibiting CDK2-cyclin E.
Studies of the expression of cyclin D3, KIP1, pRb and p107 suggest that changes in the control of the cell cycle are closely related to the pathobiology of non-Hodgkin lymphomas.
References
This page last revised 12.5.2003.
©SMUHT/PW Bishop