TY - JOUR
T1 - Cell cycle activation in p21 dependent pathway
T2 - An alternative mechanism of organophosphate induced dopaminergic neurodegeneration
AU - Wani, Willayat Yousuf
AU - Kandimalla, Ramesh J.L.
AU - Sharma, Deep Raj
AU - Kaushal, Alka
AU - Ruban, Anand
AU - Sunkaria, Aditya
AU - Vallamkondu, Jayalakshmi
AU - Chiarugi, Alberto
AU - Reddy, P. Hemachandra
AU - Gill, Kiran Dip
N1 - Funding Information:
Acknowledgements—financial assistance from the Indian Council of Medical Research, India (5/8/4-2(Env)/09-NCD-1), in the form of SRF to Willayat Yousuf Wani is acknowledged. We are thankful to the Council of Scientific and Industrial Research (37(1218)/2010) for funding this study. We are also thankful to the European Molecular Biology Organization for providing short-term fellowship to Willayat Yousuf Wani. Work presented in this article is also supported by NIH grants AG042178, AG047812 and the Garrison Family Foundation.
Funding Information:
Acknowledgements—financial assistance from the Indian Council of Medical Research, India ( 5/8/4-2(Env)/09-NCD-1 ), in the form of SRF to Willayat Yousuf Wani is acknowledged. We are thankful to the Council of Scientific and Industrial Research (37(1218)/2010) for funding this study. We are also thankful to the European Molecular Biology Organization for providing short-term fellowship to Willayat Yousuf Wani. Work presented in this article is also supported by NIH grants AG042178 , AG047812 and the Garrison Family Foundation .
Publisher Copyright:
© 2016 Elsevier B.V.
PY - 2017/7
Y1 - 2017/7
N2 - In the previous study, we demonstrated that dichlorvos induces oxidative stress in dopaminergic neuronal cells and subsequent caspase activation mediates apoptosis. In the present study, we evaluated the effect and mechanism of dichlorvos induced oxidative stress on cell cycle activation in NGF-differentiated PC12 cells. Dichlorvos exposure resulted in oxidative DNA damage along with activation of cell cycle machinery in differentiated PC12 cells. Dichlorvos exposed cells exhibited an increased expression of p53, cyclin-D1, pRb and decreased expression of p21suggesting a re-entry of differentiated cells into the cell cycle. Cell cycle analysis of dichlorvos exposed cells revealed a reduction of cells in the G 0 /G 1 phase of the cell cycle (25%), and a concomitant increase of cells in S phase (30%) and G2/M phase (43.3%) compared to control PC12 cells. Further, immunoblotting of cytochrome c, Bax, Bcl-2 and cleaved caspase-3 revealed that dichlorvos induces a caspase-dependent cell death in PC12 cells. These results suggest that Dichlorvos exposure has the potential to generate oxidative stress which evokes activation of cell cycle machinery leading to apoptotic cell death via cytochrome c release from mitochondria and subsequent caspase-3 activation in differentiated PC12 cells.
AB - In the previous study, we demonstrated that dichlorvos induces oxidative stress in dopaminergic neuronal cells and subsequent caspase activation mediates apoptosis. In the present study, we evaluated the effect and mechanism of dichlorvos induced oxidative stress on cell cycle activation in NGF-differentiated PC12 cells. Dichlorvos exposure resulted in oxidative DNA damage along with activation of cell cycle machinery in differentiated PC12 cells. Dichlorvos exposed cells exhibited an increased expression of p53, cyclin-D1, pRb and decreased expression of p21suggesting a re-entry of differentiated cells into the cell cycle. Cell cycle analysis of dichlorvos exposed cells revealed a reduction of cells in the G 0 /G 1 phase of the cell cycle (25%), and a concomitant increase of cells in S phase (30%) and G2/M phase (43.3%) compared to control PC12 cells. Further, immunoblotting of cytochrome c, Bax, Bcl-2 and cleaved caspase-3 revealed that dichlorvos induces a caspase-dependent cell death in PC12 cells. These results suggest that Dichlorvos exposure has the potential to generate oxidative stress which evokes activation of cell cycle machinery leading to apoptotic cell death via cytochrome c release from mitochondria and subsequent caspase-3 activation in differentiated PC12 cells.
KW - Cyclin-D1
KW - Dichlorvos
KW - Neurodegeneration
KW - Oxidative stress
KW - p21
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UR - http://www.scopus.com/inward/citedby.url?scp=84977533210&partnerID=8YFLogxK
U2 - 10.1016/j.bbadis.2016.05.014
DO - 10.1016/j.bbadis.2016.05.014
M3 - Article
C2 - 27262357
AN - SCOPUS:84977533210
SN - 0925-4439
VL - 1863
SP - 1858
EP - 1866
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 7
ER -