Proteins tumor suppressers

By examining some of the over one thousand tumor-causing point mutations of p53 in the light of its structure, we can identify features of p53 that are necessary for tumor suppression. The amino acids most frequently changed in cancer cells are at or near the protein-DNA interface residues that are infrequently mutated, if at all, are in general far from the DNA-binding site. 

Thymidylate synthase (TS) is the rate-limiting enzyme in the DNA synthetic pathway and the target for 5-FU and folate analogs (Figure 14.3). Compared to normal tissues, TS is often overexpressed in tumor cells, probably as a result of tumor suppression loss of function, gene amplification or other mechanisms. Acute induction of TS protein as well as stable amplification of TS-specific genes may be associated with resistance to fluoropyrimidine derivatives [118, 119], and an inverse correlation between tumor TS expression and clinical response was found [120-122]. 

Kitabayashi I, Aikawa Y, Nguyen LA, Yokoyama A, Ohki M (2001) Activation of AMLl -mediated transcription by MOZ and inhibition by the MOZ-CBP hsion protein. EMBO J 20 7184-7196 Klochendler-Yeivin A, Yaniv M (2001) Chromatin modifiers and tumor suppression. Biochim Biophys Acta 155LMI-10... 

Choi PM, Tchou-Wong KM, Weinstein IB (1990) Overexpression of protein kinase C in HT29 colon cancer cells causes growth inhibition and tumor suppression. Mol Cell Biol 10 4650-4657... 

Figure 7.20 Examples of haptens for the creation of antibodies directed toward the 6-phosphor-ylserine tumor suppressive protein p53. ...

Central to the function of the p53 protein is its abUity, as a transcription activator, to specifically bind to corresponding cis elements in the promoter region of various genes and to activate their transcription. The importance of sequence-specific DNA binding for the tumor-suppressing function of p53 became clear when the crystal structure of the complex of p53 protein and a corresponding DNA element were resolved and this structure was compared with the spectrum of known mutations of p53 protein occurring in human tumors (Cho et al., 1994). 

Fig. 14.11. Model of the function of the p53 protein. The figure summarizes in a very simplified manner two important functions of the p53 protein, which are assumed to be of importance for the tumor-suppressive activity of p53. The p53 protein is activated by DNA damage and other signals and can either bring about a halt in the cell cycle or initiate apoptosis of the cell. Activation of apoptosis can also be triggered via pathways other than the bax gene. The figure does not take into consideration the many other biochemical functions of p53, which can also be linked to the two pathways shown.

Cells have been stained successfully for nuclear proteins related to proliferation (for example, PCNA, Ki-67, and various cyclins, which will be discussed in the chapter on DNA) and to tumor suppression (for example, p53, c-myc, and the retinoblastoma gene product). They have also been stained for proteins bound to interior membrane surfaces (e.g., Bcl-2, multidrug resistance protein [MDR], and P-gly-coprotein), and many strictly cytosolic proteins have been analyzed (like tubulin, hemoglobin, surface proteins that exist intracellularly at various stages of differentiation, and many cytokines). 

MTMl (33). This molecule can be removed either by phosphorylation into P1-4,5-P2 by phosphorylation with the fS-form of P1-4K (34) or by dephosphorylation of P1-5-P by the novel form of PTEN-like proteins with selectivity toward phosphatidyh-nositol phosphorylated at the 5-position (35). Recent studies suggest a role for P1-5-P in a variety of cellular events, such as tumor suppression, response to bacterial invasion (35), and control of osmotic pressure (36). This phospholipid has been shown recently to function as a second messenger that binds to an Arabidopsis homolog of trithorax, which suggests that it may have a regulatory function that connects lipid signahng with nuclear functions (37). 

Fujiu N, You L, Xu Z et al (2007) An antagonist of dishevelled protein-protein interaction suppresses P-catenin-dependent tumor cell growth. Cancer Res 67 573-579... 

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