TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2

Tumour necrosis factor-alpha (TNF-alpha) is a proinflammatory mediator that exerts its biological functions by binding two TNF receptors (TNF-RI and TNF-RII), which initiate biological responses by interacting with adaptor and signalling proteins. Among the signalling components that associate with TNF receptors are members of the TNF-R-associated factor (TRAF) family. TRAF2 is required for TNF-alpha-mediated activation of c-Jun N-terminal kinase (JNK), contributes to activation of NF-kappaB, and mediates anti-apoptotic signals,. TNF-RI and TNF-RII signalling complexes also contain the anti-apoptotic ('inhibitor of apoptosis') molecules c-IAP1 and c-IAP2 (refs 5, 6), which also have RING domain-dependent ubiquitin protein ligase (E3) activity. The function of IAPs in TNF-R signalling is unknown. Here we show that binding of TNF-alpha to TNF-RII induces ubiquitination and proteasomal degradation of TRAF2. Although c-IAP1 bound TRAF2 and TRAF1 in vitro, it ubiquitinated only TRAF2. Expression of wild-type c-IAP1, but not an E3-defective mutant, resulted in TRAF2 ubiquitination and degradation. Moreover, E3-defective c-IAP1 prevented TNF-alpha-induced TRAF2 degradation and inhibited apoptosis. These findings identify a physiologic role for c-IAP1 and define a mechanism by which TNF-RII-regulated ubiquitin protein ligase activity can potentiate TNF-induced apoptosis.     

Hepatocyte growth factor-mediated attraction of mesenchymal stem cells for apoptotic neuronal and cardiomyocytic cells

Human bone marrow-derived mesenchymal stem cells (MSC) home to injured tissues and have regenerative capacity. In this study, we have investigated in vitro the influence of apoptotic and necrotic cell death, thus distinct types of tissue damage, on MSC migration. Concordant with an increased overall motility, MSC migrated towards apoptotic, but not vital or necrotic neuronal and cardiac cells. Hepatocyte growth factor (HGF) was expressed by the apoptotic cells only. MSC, in contrast, revealed expression of the HGF-receptor, c-Met. Blocking HGF bioactivity resulted in significant reduction of MSC migration. Moreover, recombinant HGF attracted MSC in a dose-dependent manner. Thus, apoptosis initiates chemoattraction of MSC via the HGF/c-Met axis, thereby linking tissue damage to the recruitment of cells with regenerative potential.     

Loss of CD24 expression promotes ductal branching in the murine mammary gland

CD24 is expressed on mammary stem cells and is used as a marker for their isolation, yet its function in the mammary gland still needs to be examined. Here we show that CD24 is expressed throughout the luminal epithelial cell layer, but only weakly in myoepithelial cells. During lactation, CD24 expression was suppressed within alveoli, but upregulated post-lactation, returning to a pre-pregnant spatial distribution. CD24-deficient mice exhibited an accelerated mammary gland ductal extension during puberty and an enhanced branching morphogenesis, resulting in increased furcation in the ductal structure. CD24−/− mammary epithelial cells were able to completely repopulate cleared mammary fat pads and to give rise to fully functional mammary glands. Together, these data suggest that while CD24 is expressed in mammary epithelium compartments thought to contain stem cells, CD24 is not a major regulator of mammary stem/progenitor cell function, but rather plays a role in governing branching morphogenesis.     

Debunking material induction

In this paper, we present an explanatory objection to Norton's material theory of induction, as applied to predictive inferences. According to the objection we present, there is an explanatory disconnect between our beliefs about the future and the relevant future facts. We argue that if we recognize such a disconnect, we are no longer rationally entitled to our future beliefs.     

Site and stand characteristics related to white pine blister rust in high-elevation forests of southern Idaho and western Wyoming

Successful infection of white pine species by white pine blister rust (WPBR) is contingent upon environmental conditions that are favorable to the spread and development of Cronartium ribicola . Site and stand factors related to this process have been studied elsewhere within the distribution of the disease, but few studies have concentrated on the high-elevation white pine forests of southern Idaho and western Wyoming. We found that mean summer precipitation, average tree diameter, and elevation were the most important variables in 3 logistic regression models of WPBR presence and intensity. The models were tested on a randomly chosen portion of our data set. The model with 9 variables correctly predicted categories of low-, moderate-, and high-disease incidence in 79% of cases. The 2 models with fewer variables had lower predictive efficiencies but were more parsimonious and generally easy to measure. The ability to use easily measured or remotely sensed site and stand characteristics to predict WPBR spread or intensification could be an important asset to land managers who need to decide where to focus disease mitigation efforts and predict disease effects on water quality, wildlife habitat, recreation potential, and other land-management activities.