HIV/gp120 decreases adult neural progenitor cell proliferation via checkpoint kinase-mediated cell-cycle withdrawal and G1 arrest.
Impaired adult neurogenesis has been observed in several neurodegenerative diseases, including human immunodeficiency virus (HIV-1)-associated dementia (HAD). Here we report that the HIV-envelope glycoprotein gp120, which is associated with HAD pathogenesis, inhibits proliferation of adult neural progenitor cells (aNPCs) in vitro and in vivo in the dentate gyrus of the hippocampus of HIV/gp120-transgenic mice. We demonstrate that HIV/gp120 arrests cell-cycle progression of aNPCs at the G1 phase via a cascade consisting of p38 mitogen-activated protein kinase (MAPK) --> MAPK-activated protein kinase 2 (a cell-cycle checkpoint kinase) --> Cdc25B/C. Our findings define a molecular mechanism that compromises adult neurogenesis in this neurodegenerative disorder.
Okamoto
Shu-ichi
S
Center for Neuroscience, Stem Cells, and Aging, Burnham Institute for Medical Research, La Jolla, CA 92037, USA. sokamoto@burnham.org
Kang
Yeon-Joo
YJ
Brechtel
Christopher W
CW
Siviglia
Elisa
E
Russo
Rossella
R
Clemente
Arjay
A
Harrop
Anne
A
McKercher
Scott
S
Kaul
Marcus
M
Lipton
Stuart A
SA
D015526:AIDS Dementia Complex / Q000378:metabolism / Q000821:virology; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D005260:Female; D016193:G1 Phase / Q000235:genetics / Q000502:physiology; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000502:physiology*; D015658:HIV Infections / Q000201:enzymology / Q000473:pathology* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000821:virology; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D013234:Stem Cells / Q000502:physiology*; D020687:cdc25 Phosphatases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
D015699:HIV Envelope Protein gp120; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D020687:cdc25 Phosphatases; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C514793:gp120 protein, Human immunodeficiency virus 1; C517006:Cdc25b protein, mouse; C517010:Cdc25c protein, mouse