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Non-small-cell lung cancer (NSCLC) is the most prevalent histological cancer subtype worldwide (1). As the majority of patients present with invasive, metastatic disease (2), it is vital to understand the [...]

Author(s): Julian Downward (corresponding author) All cells must continually sense their surrounding environment and make decisions on the basis of that information. Single-celled organisms must be able to tell which [...]

The role of phosphatidylinositol-3-kinase (PI(3)K) in the cellular signal transduction pathway that promotes apoptosis in fibroblasts was analyzed in rodent cells during c-Myc-induced apoptosis. Expression of a constitutively active PI(3)K in rodent cells inhibited c-Myc-induced apoptosis via Ras activation PKB/Akt downstream protein kinase activators. Furthermore, inhibition of apoptosis indicated the presence of a putative anti-apoptotic pathway from Ras to PI(3)K and PKB/Akt.

Studies of cellular targets of Ras proteins responsible for the biological effects of Ras reveal a new phosphatidylinositol-3-OH kinase (PI(3)K) that facilitates direct downstream signal transmissions from Ras. The catalytic domain of PI(3)K binds to the GTP-bound form of Ras through the Ras effector site. Growth factor-initiated generation of 3' phosphorylated phosphoinositides in PC12 cells is suppressed by dominant negative Ras mutant N17, and Ras transfection into COS cells increases PI(3)K lipid levels.

Raf appears to be a direct target enzyme of Ras. If so, it is the first such effector to be identified. The regulatory region of p74(c-raf-1) expressed as a GST fusion protein binds directly to Ras with a high affinity of 50 nM, when Ras is in the active (GTP-bound) state. Evidence that Ras can control the kinase activity of full-length Raf would prove the connection. This research does not eliminate the possibility of other effectors of Ras.

The first identification of oncogenes in cancer-causing viruses led to the observation of similar genes, called proto-oncogenes, in normal cells. One such proto-oncogene is ras, which has been identified in a wide range of species. Several related ras genes have been discovered, and although their role in the transformation of normal cells to tumor cells has been widely studied, the physiological function of ras genes in normal healthy cells has remained uncertain. Now it has been shown that the stimulation of T cells through the binding of specific antigen to their receptors involves a rapid activation of p21ras, or the 21-kilodalton protein coded by the ras gene. The activation apparently results from a decrease in the activity of GAP. GAP, or GTPase activating protein, promotes the conversion of GTP to GDP on the p21ras protein. Therefore, most of the guanine nucleotides on p21ras are in the form of GDP rather than GTP. When the T cells are stimulated, the activity of GAP is reduced, and GTP replaces GDP as the predominant nucleotide. The researchers suggest that this change in p21ras results from the activity of protein kinase C. They were able to observe that direct stimulation of protein kinase C produced results similar to those observed by stimulation of the T-cell receptor. They were unable to demonstrate any direct modification of GAP by protein kinase C, however, and propose that a GTP-exchange protein might be the direct target of the protein kinase C activity. This research is the first direct demonstration of the involvement of p21ras in normal cellular processes. It is clear, however, that further research will be necessary to work out the details. (Consumer Summary produced by Reliance Medical Information, Inc.)

The Ras guanine-nucleotide-binding (G) family of proteins controls cellular behaviour such as proliferation, survival, morphology and membrane transport. Their common mechanism is the opposing effect of stimulatory guanine-nucleotide-exchange factors (GEFs). Researchers have made a study showing control of Ras family proteins is more varied than thought and provides molecular information on that control.

The lipid kinase phosphatidylinositol-3-OH kinase or PI(3)K has a major role in signal transduction pathways, information channels initiated at cell membranes and reaching the nucleus, and may regulate gene expression and cellular proliferation. The activities of the protein kinase C family and the ribosomal protein S6 kinase, may be regulated by PI(3)K. The serine/threonine kinase known differently as protein kinase B (PKB), Akt and Rac may be stimulated by and bind directly to 3-phosphorylated phosphoinositides. The mechanisms of PI(3)K are important to understand because cancer cells result from damaged pathways.

Cells with several types of mitogens and Ras proteins involved in intracellular signalling activate ribosomal protein kinase, S6 kinase. The process of cell proliferation and carcinogenic mutation is also controlled by the Ras proteins. The S6 kinase is phosphorylated by a specific group of kinases, the activities of which depend on the Ras-MAP kinase.

How serum growth factors, GTP-binding proteins and cytoskeletal structure interact to regulate cellular processes such as cell division has been made clearer by recent research. Anne Ridley, Alan Hall and co-workers showed that the extracellular factors to actin organization actually consist of a whole array of Ras superfamily GTPases, Ras being the guanine-nucleotide-binding protein related to the Rho protein. Rho and Rac are regulatory molecules that determine the structure of actin microfilaments.

Chengchao Shou and colleagues have advanced the study of signal transduction in eukaryotic cells by successfully cloning a Ras-protein specific mammalian guanine-nucleotide-exchange or releasing factor. The cloned exchange factor will help the understanding of control mechanisms for those proteins and Ras-proteins as well as exploring the relationship between tyrosine kinases in exchange factors and growth factor receptors.

The article presents studies on the mutation in RAS genes that are common in human tumours. The studies examine the potential large-scale practical genomic screens with the use of RNA-interference technique to selectively inhibit gene expression along with the notion of the complete sequence of the human genome. Findings show that RAS-mutant cells are reliant on Serine/threorine-protein kinase (TBK1) indicating it will add up the effort to inhibit the pathway in the tumour types.