79 research outputs found
Cdc25A phosphatase: a key cell cycle protein that regulates neuron death in disease and development
Cell cycle molecules are mostly dormant in differentiated
neurons that are post-mitotic and in the G0 state of the cell cycle. However, a wealth of evidence strongly suggests that in response to a wide variety of apoptotic stimuli, including trophic factor deprivation, exposure to β-amyloid (Aβ) and DNA damage, neurons emerge from theG0 state with aberrant expression/activation of cell cycle proteins.1 This emergence is characterized by a consistent set of events related to the cell cycle that culminate in neuron death. Initial responses include
activation of G1/S cyclin-dependent kinases (Cdks), such as Cdk4 that in turn phosphorylate retinoblastoma (pRb) family proteins and lead to dissociation of repressor complexes comprising E2F and pRb proteins, so that E2F-binding genes are de-repressed. Among genes that are de-repressed by loss of E2F-Rb family complexes are the B- and C-myb transcription factors that in turn transactivate Bim, a pro-apoptotic protein that promotes caspase activation and subsequent neuron death.1â4 This set of events has been termed the âapoptotic cell cycle pathwayâ.Cell division cycle 25A (Cdc25A), a member of a family comprising Cdc25A, B and C, is a dual specificity phosphatase that dephosphorylates inhibitory phosphates on adjacent threonine and tyrosine residues of Cdks such as Cdk4.5 This step is essential for initiation of cell cycle in proliferating cells. However, it was not known whether in the non-dividing neurons, the same events would activate the apoptotic cell cycle pathway. In our recent paper published in Cell Death Discovery,6 we report several novel findings regarding the potential role of Cdc25A in neuron death. First, Cdc25A is
required for activation of the apoptotic cell cycle pathway and neuron death in response to nerve growth factor (NGF) deprivation and Aβ treatment. Second, Cdc25A acts upstream of Cdk-mediated Rb phosphorylation and caspase-3 cleavage. Third, NGF deprivation and Aβ lead to rapid increases in Cdc25A mRNA and protein levels. NGF withdrawal causes an increase in Cdc25A activity as well. These events occur at about the same time that apoptotic insults lead to Cdk4 activation and Rb phosphorylation in our experimental systems and well precede evident signs of neuron death
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Intriguing High Z'' Cocrystals of Emtricitabine
YesEmtricitabine (ECB) afforded dimorphic cocrystals (Forms I, II) of benzoic acid (BA), whereas with p-hydroxybenzoic acid (PHBA), p-aminobenzoic acid (PABA) are resulted in as high Z'' cocrystals. Intriguingly, the Z'' of cocrystals are trends from two to fourteen based on the manipulation of functional groups on the para position of BA (where H atom is replaced with that of OH or NH2 group). ECBâPABA cocrystal consists of six molecules each and two water molecules in the asymmetric unit (Z''=14) with 2D planar sheets represents the rare pharmaceutical cocrystal. The findings suggest that the increment of H bond donor(s) systematically via a suitable coformer are in correspondence with attaining high Z'' cocrystals. Further, solid state NMR spectroscopy in conjunction with single crystal X-ray diffraction are demonstrated as significant tools to enhance the understanding of the number of symmetry independent molecules in the crystalline lattice and provide insights to the mechanistic pathways of crystallization.Department of Science and Technology (DST) Fund for improvement of S & T Infrastructure (FIST) with grant no. SR/FST/CST-266/2015(c) to PS and VP. AN and VV acknowledge the Government of India under National Overseas Scholarship (2012-13) and High Commission of India, London UK for PhD studentship
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