Cell-cycle regulatory proteins

Ganoth, D., et ah. The cell-cycle regulatory protein Cksl is required For SCF( Skp2)-mediated ubiquitinylation of p27. Nat Cell Biol, 2001, 3(3),... 

Bashir, T. and Pagano, M. Aberrant ubiquitin-mediated proteolysis of cell cycle regulatory proteins and oncogenesis. Adv Cancer Res 2003, 88, 101-44. 

Bourne, Y., Watson, M. H., Hickey, M. J., Holmes, W., Rocque, W., Reed, S. I., and Tainer, J. A. (1996). Crystal structure and mutational analysis of the human CDK2 kinase complex with cell cycle-regulatory protein CksHsl, Cell 84, 863-74. 

Pagano, M. (1997). Regulation of cell cycle regulatory proteins by the ubiquitin pathway,FASEB 111, 1067-1075. 

In summary, due fo fhe large panel of cell cycle regulatory proteins regulated by HDACs at the level of either their expression or activity, the antiproliferative effect of HDAC inhibitors cannot be linked to a single mechanism of action. The relative importance of the different proteins affected by HDACs varies between tumors. In Fig. 2, a visual overview of the role of HDACs in various hallmark processes in the development of cancer is shown. 

Goldberg Y, Nassif II, Pittas A, et al. The anti-proliferative effect of sulindac and sulindac sulfide on HT-29 colon cancer cells alterations in tumor suppressor and cell cycle-regulatory proteins. Oncogene 1996 12 893-901. 

Resveratrol exerts antitumor effects partly by arresting the growth of various cancer cells in culture [Kundu and Surh, 2004]. The inhibition of ornithine decarboxylase (ODC), a biochemical hallmark of tumor promotion, has been shown to account for the antiproliferative and antitumor effects of resveratrol [Schneider et al., 2000 Ulrich et al., 2007]. Aberrant changes in cell-cycle machinery are considered as the biochemical basis of abnormal proliferation of transformed cells. Major cell-cycle regulatory proteins include various cyclins, cyclin-dependent kinases (Cdk), Cdk inhibitors, and check point kinases (Chkl... 

The ability of phytochemicals to modulate cell cycle can be useful in evaluating and optimizing cancer prevention by these compounds. Studies reported here demonstrate that phytochemicals may differentially impact cell cycle and cell number depending upon the mutations in the cancer cell. In addition, cell cycle regulatory proteins are altered by phytochemicals in ways that may explain the cell cycle modulation. The fact that structural features of flavonoids impact cell cycle modulation suggests that cell cycle modulation may be useful in identifying the most active compounds for colon cancer prevention. Finally, cell cycle modulation studies can inform us on plant modifications that may be useful for nutritional enhancement. 

Milde-Langosch K, Bamberger AM, Methner C, Rieck G, Loning T. Expression of cell cycle-regulatory proteins rb, pl6/MTSl, p27/KIPl, p21/WAFl, cyclin Dl and cyclin E in breast cancer correlations with expression of activating protein-1 family members. In t. J. Cancer 2000 87 468-472. 

Various t pes of DNA damage, such as a break in one of the strands of the double helix, activates p53, and provokes the cell cycle to halt just prior to the S phase (Huang et ai, 1996). Once activated, p53 provokes the transcription of several genes. These genes code for proteins that interfere with cell cycle regulatory proteins and with DNA polymerase. The result is a pause in the cell cycle, which gives our DNA repair enzymes a chance to fix the damaged bases or broken strands. 

For application with triple-quadrapole and especially (J-LIT instruments, a selected-reaction monitoring (SRM) procedure was developed for the sensitive and selective detection of phosphopeptides in proteomes with known amino-acid sequences [26]. A list of SRM transitions of potential phosphopeptides is generated for all expected tryptic peptides in the mixtme with Ser, Thr, or Tyr and for double-and triple-charge ions in the mass range of m/z 400-1600. The number of transitions included is limited by the maximum cycle time of 10 s, which assures that peptides in a 30 s wide peak are at least analysed twice. The procedure was applied to the cell cycle regulatory protein Cyclin B from Schizosaccharomyces pombe. 

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.

The complex of Siro and the intracellular immunophilin FK-BP12 modulates the immune response by combining with the specific cell-cycle regulatory protein mTOR and... 

Another simple approach for the detection of noncovalent interactions is to compare the peptide maps produced by proteolysis of the target protein and its complex with other ligands. This approach, also known as epitope mapping, relies on the fact that the two maps differ qualitatively because the contact regions of the interacting proteins are shielded from the protease s activity in the complex. An illustrative example is the detection of protein-protein interaction between a protein representing the kinase inhibitory domain of the cell cycle regulatory protein (p21-B) and cyclin-dependent kinase 2 (cdk).164... 

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