Phosphatase tumor-activated

Waldmann et al. have synthesised a library of analogues of the anti-tumor active phosphatase inhibitor dysidiolide (16) [18]. A notable feature of this 11-step reaction sequence on solid-phase is that a wide range of transformations with vastly differing requirements could successfully be developed. Key transformations of the synthesis include an asymmetric... 

The ability of 3-phosphoinositides to stimulate cell proliferation/survival via activation of Akt is countered by the 3-phosphatase PTEN, which hydrolyzes PI(3,4)P2 and PI(3,4,5)P3. A link between PTEN activity and 3-phosphoinositide content in cells is evident from the observations that (a) overexpression of PTEN results in a dramatic reduction in the cellular content of these lipids, and (b) 3-phosphoinositide concentrations are greatly elevated in mammalian PTEN-null cell lines [28]. Cells in which PTEN activity is reduced have increased tumori-genic properties, since Akt inhibits apoptosis and promotes cell survival. Conversely, PTEN activity programs the fate of the cell toward apoptosis. Mutations of PTEN have been shown to occur in a wide range of tumor types, but with a particularly high frequency in glioblastomas. 

Alkaline phosphatase is an enzyme represented by various isoforms in many tissues such as liver, bone, intestine, placenta, some tumors and in leukocytes. Addition of 1 mM levamisole to the chromogen/substrate will inhibit endogenous alkaline phosphatase activity, with the exception of the intestinal isoform. If necessary, this can be blocked with a weak acid wash, such as 0.03 0.5 N HC1 or 1 M citric acid. 

Freeman, D. J., et al., PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell, 2003, 3(2), 117-30. 

Provenge is a cancer vaccine using cell therapy technique. Dendritic cells are removed from patients. These cells are treated with the prostate-specific antigen prostatic acid phosphatase (PAP), which is present in 95% of prostate cancer cases. The activated dendritic cells are returned to the patients and they stimulate the T cells to destroy cancer cells expressing the PAP, thus treating the tumor. 

Cyclosporine can bind to the cytosolic protein cy-tophilin C. This drug-protein complex inhibits cal-cineurin phosphatase activity, which leads to a decreased synthesis and release of several cytokines, including interleukins IL-2, IL-3, IL-4, interferon-a, and tumor necrosis factor. 

The great importance of PtdIns(3,4,5)P3 metabolism for growth regulation is illustrated by the observation that an enzyme of PtdIns(3,4,5)P3 metabolism has been identified as a tumor suppressor protein (Wu et al., 1998). PTEN tumor suppressor protein has lipid phosphatase activity that is specific for hydrolysis of PtdIns(3,4,5)P3. It is assumed that PTEN lipid phosphatase is a negative regulator of the Akt pathway by lowering the concentration of PtdIns(3,4,5)P3 and counteracting stimulation of Akt kinase. 

Fig. 6.12. Formation and function of the messenger substance ceramide. The starting point for the synthesis of ceramide is sphingomyelin, which is converted to phosphocholine and ceramide by the action of a sphingomyelinase. Sphingomyelinase is activated via a pathway starting from tumor necrosis factor a (TNFa) and its receptor. Ceramide serves as an activator of protein kinases and protein phosphatases. RI fatty add side chain.

Fig. 13.11. Substrates and phase-spedfic activation of CDKs in the ceU cycle. An overview is shown of the phase-specific activation of the most important CDK-cychn complexes and of selected substrates. The arrows indicate activation and phosphorylation. CDK cycMn-dependent protein kinase p53 tumor suppressor p53 pRb tumor suppressor pRb CDC25 CDC25 phosphatase TFIIIB transcription factor TFIIIB R restriction point.

The potent toxin microcystin [blue-green algae inhibit one of the phosphatases (PP2A)] increases mitogenic activity and so is a tumor promoter at low-level exposures. The liver toxicity at high levels of acute exposure is probably also due to disturbances in protein phosphorylation. 

Microcystins are extremely potent inhibitors of protein phosphatases, active at the level of 0.2 nM (2 x 10-10 M). Coupled with the active uptake into the liver, this means that microcystins are extremely toxic. As well as being hepatotoxic, they are also tumor promoters. 

---