One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively.
AbstractsReactive oxygen species (ROS) and intrinsic antioxidant defense systems play an important role in both physiological cell signaling processes and many pathological conditions, including neurodegenerative disorders and oxygen-toxicity. Beside the glutathione-system several other redox-modulating proteins are known to be involved in redox-homeostases. The aim of this study was to evaluate potential alterations within the thioredoxin/peroxiredoxin system after exposures to nonphysiologic high oxygen levels in the developing rat brain. Methods Six-days old Wistar rats were exposed to 80% oxygen for 6, 12, 24 or 48 hours and littermates kept in room air served as controls (n=6-8). Brains (excluding cerebellum) were evaluated after perfusion with PBS and dissection of both hemispheres for RNA and protein analyses. Results We demonstrate that elevated oxygen concentrations change the balance of the ROS-dependent thioredoxin/peroxiredoxin system. Oxygen-toxicity significantly induced upregulation of peroxiredoxins in infant rat brain. In parallel, hyperoxia reduced the level of DJ-1, a hydroperoxide-responsive protein. Discussion These findings are highly relevant from a clinical aspect because oxygen administration to neonates is often inevitable, and we recommend that every effort should be made in neonatal medicine to limit exposure of these immature babies to high oxygen concentrations. These results may also contribute to receive optimal therapeutical approaches to ameliorate oxygen toxicity. Purpose Assessment of intima-media thickness (IMT) of the aorta and carotid artery in appropriate for gestational age (AGA) infants during the first 6 months of life after very preterm birth. Methods Longitudinal ultrasound assessment including 21 very preterm and 29 infants born at term (all AGA) during a six-months period corresponding to the third trimester of pregnancy and the first 3 months after term, measuring aortic and carotid IMT by an angle-corrected M-Mode, and assessment of blood pressure at final follow-up. Results No differences in aortic or carotid IMT or blood pressure measurements were found between the two groups. However, in relation to vessel lumen diameter, IMT is significantly higher in both arteries in infants born preterm (p=0.003 for aorta and p=0.001 for carotid artery). Conclusion In relation to vessel diameter, infants born preterm show thickening of the intima-media in the great arteries. It remains to be established whether this relative intima-media thickening persists into childhood and may be a risk marker for future cardiovascular disease among subjects born preterm. AORTIC AND CAROTID INTIMA-MEDIA THICKENING IN APPROPRIATE-FOR-GESTATIONAL AGE PRETERM NEWBORNS WITH ADEQUATE BUT LOW BIRTH WEIGHT
AbstractsReactive oxygen species (ROS) and intrinsic antioxidant defense systems play an important role in both physiological cell signaling processes and many pathological conditions, including neurodegenerative disorders and oxygen-toxicity. Beside the glutathione-system several other redox-modulating proteins are known to be involved in redox-homeostases. The aim of this study was to evaluate potential alterations within the thioredoxin/peroxiredoxin system after exposures to nonphysiologic high oxygen levels in the developing rat brain. Methods Six-days old Wistar rats were exposed to 80% oxygen for 6, 12, 24 or 48 hours and littermates kept in room air served as controls (n=6-8). Brains (excluding cerebellum) were evaluated after perfusion with PBS and dissection of both hemispheres for RNA and protein analyses. Results We demonstrate that elevated oxygen concentrations change the balance of the ROS-dependent thioredoxin/peroxiredoxin system. Oxygen-toxicity significantly induced upregulation of peroxiredoxins in infant rat brain. In parallel, hyperoxia reduced the level of DJ-1, a hydroperoxide-responsive protein. Discussion These findings are highly relevant from a clinical aspect because oxygen administration to neonates is often inevitable, and we recommend that every effort should be made in neonatal medicine to limit exposure of these immature babies to high oxygen concentrations. These results may also contribute to receive optimal therapeutical approaches to ameliorate oxygen toxicity. Purpose Assessment of intima-media thickness (IMT) of the aorta and carotid artery in appropriate for gestational age (AGA) infants during the first 6 months of life after very preterm birth. Methods Longitudinal ultrasound assessment including 21 very preterm and 29 infants born at term (all AGA) during a six-months period corresponding to the third trimester of pregnancy and the first 3 months after term, measuring aortic and carotid IMT by an angle-corrected M-Mode, and assessment of blood pressure at final follow-up. Results No differences in aortic or carotid IMT or blood pressure measurements were found between the two groups. However, in relation to vessel lumen diameter, IMT is significantly higher in both arteries in infants born preterm (p=0.003 for aorta and p=0.001 for carotid artery). Conclusion In relation to vessel diameter, infants born preterm show thickening of the intima-media in the great arteries. It remains to be established whether this relative intima-media thickening persists into childhood and may be a risk marker for future cardiovascular disease among subjects born preterm. AORTIC AND CAROTID INTIMA-MEDIA THICKENING IN APPROPRIATE-FOR-GESTATIONAL AGE PRETERM NEWBORNS WITH ADEQUATE BUT LOW BIRTH WEIGHT
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