The TNF and TNF receptor superfamilies: integrating mammalian biology.

Signal transduction by tumor necrosis factor and its relatives

Cancer cells often develop resistance to chemotherapy or irradiation through mutations in the p53 tumour-suppressor gene, which prevent apoptosis induction in response to cellular damage. Death receptors — members of the tumour-necrosis factor receptor (TNFR) superfamily — signal apoptosis independently of p53. Decoy receptors, by contrast, are a non-signalling subset of the TNFR superfamily that attenuate death-receptor function. Agents that are designed to activate death receptors (or block decoy receptors) might therefore be used to kill tumour cells that are resistant to conventional cancer therapies.

Targeting death and decoy receptors of the tumour-necrosis factor superfamily

Cl− channels reside both in the plasma membrane and in intracellular organelles Their functions range from ion homeostasis to cell volume regulation, transepithelial transport, and regulation of e

https://www.leibniz-fmp.de/fileadmin/user_upload/Physiology_and_Pathology_of_Ion_Transport/documents/PhysRev2002.pdf

Molecular Structure and Physiological Function of Chloride Channels

Osteoarthritis (OA) is the most common chronic disease of human joints. The basis of pathologic changes involves all the tissues forming the joint; already, at an early stage, it has the nature of inflammation with varying degrees of severity. An analysis of the complex relationships indicates that the processes taking place inside the joint are not merely a set that (seemingly) only includes catabolic effects. Apart from them, anti-inflammatory anabolic processes also occur continually. These phenomena are driven by various mediators, of which the key role is attributed to the interactions within the cytokine network. The most important group controlling the disease seems to be inflammatory cytokines, including IL-1β, TNFα, IL-6, IL-15, IL-17, and IL-18. The second group with antagonistic effect is formed by cytokines known as anti-inflammatory cytokines such as IL-4, IL-10, and IL-13. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of OA with respect to inter- and intracellular signaling pathways is still under investigation. This paper summarizes the current state of knowledge. The cytokine network in OA is put in the context of cells involved in this degenerative joint disease. The possibilities for further implementation of new therapeutic strategies in OA are also pointed.

/pdf/the-role-of-inflammatory-and-anti-inflammatory-cytokines-in-3au3sectyv.pdf

The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis.

Tumour Necrosis Factor alpha (TNF alpha), is an inflammatory cytokine produced by macrophages/monocytes during acute inflammation and is responsible for a diverse range of signalling events within cells, leading to necrosis or apoptosis The protein is also important for resistance to infection and cancers TNF alpha exerts many of its effects by binding, as a trimer, to either a 55 kDa cell membrane receptor termed TNFR-1 or a 75 kDa cell membrane receptor termed TNFR-2 Both these receptors belong to the so-called TNF receptor superfamily The superfamily includes FAS, CD40, CD27, and RANK The defining trait of these receptors is an extra cellular domain comprised of two to six repeats of cysteine rich motifs Additionally, a number of structurally related "decoy receptors" exist that act to sequester TNF molecules, thereby rescuing cells from apoptosis The crystal structures of TNF alpha, TNF beta, the extracellular domain of TNFR-1 (denoted sTNFR-1), and the TNF beta sTNFR-1 complex have been defined by crystallography This article will review the structure/function relationships of the TNF alpha and the TNF receptor superfamily It will also discuss insights as to how structural features play a role in the pleiotropic effects of TNF alpha

TNF alpha and the TNF receptor superfamily: structure-function relationship(s).

P-glycoprotein (Pgp) is a transmembrane transporter causing efflux of a number of chemically unrelated drugs and is responsible for resistance to a variety of anticancer drugs during chemotherapy. Pgp overexpression in cells is also associated with volume-activated chloride channel activity; Pgp is thought to regulate such activity. Reversible phosphorylation is a possible mechanism for regulating the transport and chloride channel regulation functions of Pgp. Protein kinase C (PKC) is a good candidate for inducing such phosphorylation. Hierarchical multiple phosphorylation (e.g. of different serines and with different PKC isoforms) may shuttle the protein between its different states of activity (transport or channel regulation). Cell volume changes may trigger phosphorylation of Pgp at sites causing inhibition of transport. The possible regulation of chloride channels by Pgp and the potential involvement of reversible phosphorylation in such regulation is reviewed.

Regulation of volume-activated chloride channels by P-glycoprotein: phosphorylation has the final say!

Man to Trypanosome: The tubulin tyrosination/detyrosination cycle revisited

The tubulin tyrosination/detyrosination cycle is a well-established posttranslational modification, which is carried out by two enzymes: Tubulin Tyrosine Ligase (TTL) and Tubulin Tyrosine Carboxypeptidase (TTCP) In this paper, I present evidence suggesting that the cycle itself is under the hierarchical control of reversible phosphorylation and that PKC mediated phosphorylation of TTL inhibits its activity, thereby preventing tubulin tyrosination Phosphorylation of TTL is predicted to occur in a postulated Mg(++)/-ATP binding fold, leading to inhibition of Mg(++)/ATP binding and TTL mediated catalysis The implications of such control are also discussed

Haitham T. Idriss

Papers

TNF alpha and the TNF receptor superfamily: structure-function relationship(s).

Regulation of volume-activated chloride channels by P-glycoprotein: phosphorylation has the final say!

Man to Trypanosome: The tubulin tyrosination/detyrosination cycle revisited

Phosphorylation of tubulin tyrosine ligase: a potential mechanism for regulation of alpha-tubulin tyrosination.

Do TNF-α-Insensitive Cancer Cells Escape α-Tubulin Nitrotyrosination?