One signal that is overactivated in a wide range of tumour types is the production of a phospholipid, phosphatidylinositol (3,4,5) trisphosphate, by phosphatidylinositol 3-kinase (PI3K) This lipid and the protein kinase that is activated by it — AKT — trigger a cascade of responses, from cell growth and proliferation to survival and motility, that drive tumour progression Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype

The phosphatidylinositol 3-Kinase AKT pathway in human cancer.

The Tumor Suppressor, PTEN/MMAC1, Dephosphorylates the Lipid Second Messenger, Phosphatidylinositol 3,4,5-Trisphosphate

Elevated rates of reactive oxygen species (ROS) have been detected in almost all cancers, where they promote many aspects of tumour development and progression. However, tumour cells also express increased levels of antioxidant proteins to detoxify from ROS, suggesting that a delicate balance of intracellular ROS levels is required for cancer cell function. Further, the radical generated, the location of its generation, as well as the local concentration is important for the cellular functions of ROS in cancer. A challenge for novel therapeutic strategies will be the fine tuning of intracellular ROS signalling to effectively deprive cells from ROS-induced tumour promoting events, towards tipping the balance to ROS-induced apoptotic signalling. Alternatively, therapeutic antioxidants may prevent early events in tumour development, where ROS are important. However, to effectively target cancer cells specific ROS-sensing signalling pathways that mediate the diverse stress-regulated cellular functions need to be identified. This review discusses the generation of ROS within tumour cells, their detoxification, their cellular effects, as well as the major signalling cascades they utilize, but also provides an outlook on their modulation in therapeutics.

/pdf/reactive-oxygen-species-in-cancer-2cc2eau8py.pdf

Reactive oxygen species in cancer

Negative Regulation of PKB/Akt-Dependent Cell Survival by the Tumor Suppressor PTEN

/pdf/pathology-and-genetics-of-tumours-of-the-digestive-system-3xy9cwrc3c.pdf

Pathology and genetics of tumours of the digestive system

It has long been postulated that protein tyrosine phosphatases may act as tumor suppressors because of their ability to counteract the oncogenic actions of protein tyrosine kinases. Here we report the cloning and characterization of a novel human protein tyrosine phosphatase, TEP1. TEP1 contains the protein tyrosine phosphatase signature motif, and we show that it possesses an intrinsic protein tyrosine phosphatase activity. TEP1 also shares extensive homology with tensin, a cytoskeletal protein localized to focal adhesions, and with auxilin, a protein involved in synaptic vesicle transport. Immunofluorescence studies show that TEP1 is a cytoplasmic protein. The abundance of TEP1 transcription is altered in many transformed cells. In the transforming growth factor β-sensitive cells, TEP1 expression is rapidly down-regulated by transforming growth factor β, a cytokine shown to be involved in regulating cell adhesion and cell motility. We have also mapped the gene encoding TEP1 to chromosome 10q23, a locus that is frequently deleted in a variety of human cancers. TEP1 protein is identical to the protein encoded by the candidate tumor suppressor gene PTEN/MMAC1. Our functional studies of the TEP1 protein suggest that its tumor suppressor function may associate with its intrinsic protein tyrosine phosphatase activity and its cytoplasmic localization.

/pdf/tep1-encoded-by-a-candidate-tumor-suppressor-locus-is-a-2s6fbqdned.pdf

TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta.

To investigate the molecular basis of PTEN-mediated tumor suppression, we introduced a null mutation into the mouse Pten gene by homologous recombination in embryonic stem (ES) cells. Pten−/− ES cells exhibited an increased growth rate and proliferated even in the absence of serum. ES cells lacking PTEN function also displayed advanced entry into S phase. This accelerated G1/S transition was accompanied by down-regulation of p27KIP1, a major inhibitor for G1 cyclin-dependent kinases. Inactivation of PTEN in ES cells and in embryonic fibroblasts resulted in elevated levels of phosphatidylinositol 3,4,5,-trisphosphate, a product of phosphatidylinositol 3 kinase. Consequently, PTEN deficiency led to dosage-dependent increases in phosphorylation and activation of Akt/protein kinase B, a well-characterized target of the phosphatidylinositol 3 kinase signaling pathway. Akt activation increased Bad phosphorylation and promoted Pten−/− cell survival. Our studies suggest that PTEN regulates the phosphatidylinositol 3,4,5,-trisphosphate and Akt signaling pathway and consequently modulates two critical cellular processes: cell cycle progression and cell survival.

https://www.pnas.org/content/pnas/96/11/6199.full.pdf

PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway

Genetic deletion of the Pten tumor suppressor gene promotes cell motility by activation of Rac1 and Cdc42 GTPases.

Cultivated maize (Zea mays) and several other members of the Tribe Andropogoneae produce unisexual florets. In maize, the formation of two staminate florets in each spikelet on the tassel and a single pistillate floret in each spikelet on the ear includes a pistil abortion process that requires the action of the TASSELSEED2 gene. In Eastern gamagrass (Tripsacum dactyloides) the GYNOMONOECIOUS SEX FORM1 gene appears to perform a similar role in pistil abortion. These genes were shown to be homeologs by restriction fragment length polymorphism mapping and by the failure of the gsf1 and ts2 alleles to complement one another in intergeneric hybrids. Molecular analysis of the gsf1 allele shows that it is caused by a 1.4-kb deletion mutation. Both TASSELSEED2 and GYNOMONOECIOUS SEX FORM1 show similar expression patterns in subepidermal cells of pistils just before abortion. These results suggest that the formation of staminate florets in the Andropogoneae represents a monophyletic trait.

https://www.pnas.org/content/pnas/94/8/4217.full.pdf

Da-Ming Li

Papers

TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta.

PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway

Genetic deletion of the Pten tumor suppressor gene promotes cell motility by activation of Rac1 and Cdc42 GTPases.

Evidence for a common sex determination mechanism for pistil abortion in maize and in its wild relative Tripsacum