Vav1 GEF activity is required for T cell mediated allograft rejection.

The GDP exchange factor (GEF) Vav1 is a central signal transducer downstream of the T cell receptor and has been identified as a key factor for T cell activation in the context of allograft rejection. Vav1 has been shown to transduce signals both dependent and independent of its GEF function. The most promising approach to disrupt Vav1 activity by pharmacological inhibition would be to target its GEF function.

Vav1 couples the T cell receptor to cAMP response element activation via a PKC-dependent pathway.

The transcription factor cAMP-responsive element binding protein (CREB) is a regulator of the expression of several genes important for lymphocyte activation and proliferation. However, the proximal signaling events leading to activation of CREB in T cells upon antigen receptor stimulation remain unknown. Here we identify a role for Vav1 in the activation of the cAMP response element (CRE), the binding site for CREB.

Looking beyond death: a morphogenetic role for the TNF signalling pathway.

Tumour necrosis factor alpha (TNFalpha) is a pro-inflammatory mediator with the capacity to induce apoptosis. An integral part of its apoptotic and inflammatory programmes is the control of cell shape through modulation of the cytoskeleton, but it is now becoming apparent that this morphogenetic function of TNF signalling is also employed outside inflammatory responses and is shared by the signalling pathways of other members of the TNF-receptor superfamily. Some proteins that are homologous to the components of the TNF signalling pathway, such as the adaptor TNF-receptor-associated factor 4 and the ectodysplasin A receptor (and its ligand and adaptors), have dedicated morphogenetic roles.

PtdIns(4,5)P-restricted plasma membrane localization of FAN is involved in TNF-induced actin reorganization.

The WD-repeat protein factor associated with nSMase activity (FAN) is a member of the family of TNF receptor adaptor proteins that are coupled to specific signaling cascades. However, the precise functional involvement of FAN in specific cellular TNF responses remain unclear. Here, we report the involvement of FAN in TNF-induced actin reorganization and filopodia formation mediated by activation of Cdc42.

NF-kappaB-independent down-regulation of XIAP by bortezomib sensitizes HL B cells against cytotoxic drugs.

The proteasome inhibitor bortezomib has been shown to possess promising antitumor activity and significant efficacy against a variety of malignancies. Different studies demonstrated that bortezomib breaks the chemoresistance in different tumor cells basically by altering nuclear factor-kappaB (NF-kappaB) activity. NF-kappaB has been shown to be constitutively active in most primary Hodgkin-Reed-Sternberg (H-RS) cells in lymph node sections and in Hodgkin lymphoma (HL) cell lines and was suggested to be a central molecular switch in apoptosis resistance in HL.

Acid sphingomyelinase is indispensable for UV light-induced Bax conformational change at the mitochondrial membrane.

Ultraviolet light-induced apoptosis can be caused by DNA damage but also involves immediate-early cell death cascades characteristic of death receptor signaling. Here we show that the UV light-induced apoptotic signaling pathway is unique, targeting Bax activation at the mitochondrial membrane independent of caspase-8 or cathepsin D activity. Cells deficient in acid sphingomyelinase (ASMase) do not show UV light-induced Bax activation, cytochrome c release, or apoptosis.