Retinoblastoma protein , cell cycle

Figure 1 Overview of the different phases of the cell cycle. Quiescent cells are in GO phase and reenter the cell cycle at Gl during which cells prepare for DNA synthesis. After passing the restriction point in late Gl cells are committed to enter S phase, during which DNA replication occurs. Cells in G2 phase prepare for mitosis (M phase). Cell cycle progression is controlled by various positive and negative cell cycle regulatory proteins including cyclins (A, B, D, E) cyclin dependent kinases (cdk 1,2, 4, 6) cdk inhibitors (p15, p16, p18, p19, p21, p27, p57), retinoblastoma (Rb) and p53.

Puga, A., et. al., Aromatic hydrocarbon receptor interaction with the retinoblastoma protein potentiates repression of E2F-dependent transcription and cell cycle arrest, J. Biol. Chem., 275, 2943, 2000. 

Figure 26.1 Immortalization of human cells Cells enter replicative senescence at mortality stage 1 (Ml Hayflick limit) after about 60 population doublings (PD). The protein p 16 accumulates in senescent cells. The simian virus 40 (SV40) large T antigen as well as the human papilloma virus (HPV) type 16-E6 and E7 proteins sequester the retinoblastoma protein (Rb) and/or p53 constitutively releases the transcription factor E2F. E2F induces expression proteins required for progression through Gl/S transition, thus the cells escape cell cycle arrest. At mortality stage 2 (M2), transformed cells must overcome senescence and crisis before they are immortalized. This is likely to involve the activation of telomerase either by the introduction of hTERT cDNA or by a genetic change that activates telomerase.

Figure 21.16 k diagram of the mechanism by which retinoblastoma protein (Rb) regulates transcription factor activity. The rb protein binds to the transcription factor, which forms a complex in which the transcription factor for three genes is inactive. Phosphorylation of Rb by a cell division cycle kinase results in dissociation of transcription factor from the complex and hence activation. 

Weinberg, R.A. The retinoblastoma protein and cell cycle control (1995) Cell 81, 323-330... 

We have examined how cells maintain close control of CDK activity, but how does the activity of CDK control the cell cycle The list of target proteins that CDKs are known to act upon continues to grow, and much remains to be learned. But we can see a general pattern behind CDK regulation by inspecting the effect of CDKs on the structures of laminin and myosin and on the activity of retinoblastoma protein. 

Herwig, S. Strauss, M. (1997) The retinoblastoma protein a master regulator of cell cycle, differentiation and apoptosis. Eur. J. Biochem. 246, 581-601. 

Several effects of forskolin on B-lymphocytes, the cells of the immune system responsible for the production of immunoglobulins, have further been reported. This diterpene was found to inhibit cellular proliferation of B cells stimulated either by antibodies to surface immunoglobulins (anti-mu), and an antibody to CD20 antigen or 12-O-tetradecanoyl phorbol 13-acetate [219]. There was also a clear inhibition of G1 entry and DNA synthesis, and forskolin maintained its inhibitory effect even when added later after anti-mu stimulation. Additionally, no differences were found in the inhibitory effect of forskolin on neoplastic B cells, as compared to the responses of normal cells. Growth inhibition associated with an accumulation of cells in G1 was later found when cells of the B-lymphoid precursor cell line Reh were incubated with forskolin [220]. In that study, a delay of cells in G2/M prior to G1 arrest was observed, suggesting that important restriction points located in the G1 and G2 phases of the cell cycle may be controlled by forskolin (due to cAMP levels elevation). In a subsequent study [221], it was found that the arrest of Reh cells was accompanied by rapid dephosphorylation of retinoblastoma protein, which was suggested to be a prerequisite for the forskolin mediated arrest of these cells in Gl. 

Cobrinik D, Dowdy SF, Hinds PW et al. The retinoblastoma protein and the regulation of cell cycling. TIBS 1992 17 312. 

The RB gene encodes a transcriptional co-repressor which forms a complex with the cell-cycle-regulating transcription factor E2F (members of the E2F family of transcriptional activators control the genes involved in the Gj/S transition and in DNA replication 20 see Chapter 12). The RB—E2F transcriptional complex contains additional factors, such as the histone deacetylase, HDACl, which facilitates access of the transcriptional complex to E2F-responsive gene promoters, such as the cycKn E promoter. pRB and HDACl act in concert and repress the cyclin E promoter. i Hence the retinoblastoma protein (pRB) is a tumour-suppressor that represses gene expression in concert with a histone deacetylase, by modulating the architecture of chromatin (Fig. 15.4). The pRB- E2F transcriptional complex also represses transcription of RNA polymerase III22 (see also Chapter 9). 

W. R. Sellers, J. W. Rodgers, and W. G. Kaelin Jr. A potent transrepression domain in the retinoblastoma protein induces a cell cycle arrest when bound to E2F sites. Pmc Nad Acad Set, USA, 92 (25), 11544-11548, 1995. 

---