title: Role and regulation of Cdc25A phosphatase in neuron death induced by NGF deprivation orβ-amyloid.
abstract: Neuron death during development and in Alzheimer's disease (AD) is associated with aberrant regulation/induction of cell cycle proteins. However, the proximal events in this process are unknown. Cell cycle initiation requires dephosphorylation of cyclin-dependent kinases by cell division cycle 25A (Cdc25A). Here, we show that Cdc25A is essential for neuronal death in response to NGF deprivation orβ-amyloid (Aβ) treatment and describe the mechanisms by which it is regulated in these paradigms. Cdc25A mRNA, protein and Cdc25A phosphatase activity were induced by NGF deprivation and Aβtreatment. Enhanced Cdc25A expression was also observed in rat brains infused with Aβand in Aβ-overexpressing AβPPswe-PS1dE9 mice. In cultured neurons Cdc25A inhibition by chemical inhibitors or shRNA prevented cell death and neurite degeneration caused by NGF deprivation or Aβ. Additionally, Cdc25A inhibition diminished distal signaling events including Cdk-dependent elevation of phospho-pRb and subsequent caspase-3 activation. Mechanism studies revealed that Cdc25A induction by NGF deprivation and Aβis mediated by activation of Forkhead transcription factors that in turn suppress miR-21, a negative regulator of Cdc25A. Our studies thus identify Cdc25A as a required upstream element of the apoptotic cell cycle pathway that is required for neuron death in response to trophic factor deprivation and to Aβexposure and therefore as a potential target to suppress pathologic neuron death.
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology , 4 Raja S. C. Mullick Road, Kolkata 700 032, India.
authors.forename: Nandini
authors.initials: N
authors.lastname: Chatterjee
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology , 4 Raja S. C. Mullick Road, Kolkata 700 032, India.
authors.forename: Priyankar
authors.initials: P
authors.lastname: Sanphui
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center , New York, NY 10032, USA.
authors.forename: Stav
authors.initials: S
authors.lastname: Kemeny
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center , New York, NY 10032, USA.
authors.forename: Lloyd A
authors.initials: LA
authors.lastname: Greene
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology , 4 Raja S. C. Mullick Road, Kolkata 700 032, India.
authors.forename: Subhas C
authors.initials: SC
authors.lastname: Biswas