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PRC2 loss amplifies Ras signaling in cancer
Baude, Annika,Lindroth, Anders M,Plass, Christoph Nature Pub. Co 2014 Nature genetics Vol.46 No.11
The histone-modifying PRC2 complex has an ambiguous role in cancer, bearing both oncogenic and tumor-suppressive features depending on cell type. Studies of malignant peripheral nerve sheath tumors (MPNSTs) have now identified loss-of-function mutations altering PRC2 subunits, leading to the amplification of Ras-driven transcription and conferring vulnerability to BRD4 inhibitors.
Amini, Mandana,Ma, Chun-lei,Farazifard, Rasoul,Zhu, Guoqi,Zhang, Yi,Vanderluit, Jacqueline,Zoltewicz, Joanna Susie,Hage, Fadi,Savitt, Joseph M.,Lagace, Diane C.,Slack, Ruth S.,Beique, Jean-Claude,Baud Society for Neuroscience 2013 The Journal of neuroscience Vol.33 No.13
<P>Ubiquitous classical (typical) calpains, calpain-1 and calpain-2, are Ca<SUP>+2</SUP>-dependent cysteine proteases, which have been associated with numerous physiological and pathological cellular functions. However, a clear understanding of the role of calpains in the CNS has been hampered by the lack of appropriate deletion paradigms in the brain. In this study, we describe a unique model of conditional deletion of both calpain-1 and calpain-2 activities in mouse brain, which more definitively assesses the role of these ubiquitous proteases in brain development/function and pathology. Surprisingly, we show that these calpains are not critical for gross CNS development. However, calpain-1/calpain-2 loss leads to reduced dendritic branching complexity and spine density deficits associated with major deterioration in hippocampal long-term potentiation and spatial memory. Moreover, calpain-1/calpain-2-deficient neurons were significantly resistant to injury induced by excitotoxic stress or mitochondrial toxicity. Examination of downstream target showed that the conversion of the Cdk5 activator, p35, to pathogenic p25 form, occurred only in the presence of calpain and that it played a major role in calpain-mediated neuronal death. These findings unequivocally establish two central roles of calpain-1/calpain-2 in CNS function in plasticity and neuronal death.</P>
Blunted hypoxic pulmonary vasoconstriction in experimental neonatal chronic lung disease.
Rey-Parra, Gloria Juliana,Archer, Stephen L,Bland, Richard D,Albertine, Kurt H,Carlton, David P,Cho, Soo-Chul,Kirby, Beth,Haromy, Al,Eaton, Farah,Wu, Xichen,Thé,baud, Bernard American Lung Association 2008 American journal of respiratory and critical care Vol.178 No.4
<P>RATIONALE: Neonatal chronic lung disease (CLD), caused by prolonged mechanical ventilation (MV) with O(2)-rich gas, is the most common cause of long-term hospitalization and recurrent respiratory illness in extremely premature infants. Recurrent episodes of hypoxemia and associated ventilator adjustments often lead to worsening CLD. The mechanism that causes these hypoxemic episodes is unknown. Hypoxic pulmonary vasoconstriction (HPV), which is partially controlled by O(2)-sensitive voltage-gated potassium (K(v)) channels, is an important adaptive response to local hypoxia that helps to match perfusion and ventilation in the lung. OBJECTIVES: To test the hypothesis that chronic lung injury (CLI) impairs HPV. METHODS: We studied preterm lambs that had MV with O(2)-rich gas for 3 weeks and newborn rats that breathed 95%-O(2) for 2 weeks, both of which resulted in airspace enlargement and pulmonary vascular changes consistent with CLD. MEASUREMENTS AND MAIN RESULTS: HPV was attenuated in preterm lambs with CLI after 2 weeks of MV and in newborn rats with CLI after 2 weeks of hyperoxia. HPV and constriction to the K(v)1.x-specific inhibitor, correolide, were preferentially blunted in excised distal pulmonary arteries (dPAs) from hyperoxic rats, whose dPAs exhibited decreased K(v)1.5 and K(v)2.1 mRNA and K(+) current. Intrapulmonary gene transfer of K(v)1.5, encoding the ion channel that is thought to trigger HPV, increased O(2)-sensitive K(+) current in cultured smooth muscle cells from rat dPAs, and restored HPV in hyperoxic rats. CONCLUSIONS: Reduced expression/activity of O(2)-sensitive K(v) channels in dPAs contributes to blunted HPV observed in neonatal CLD.</P>