PMID- 21504794
OWN - NLM
STAT- MEDLINE
DCOM- 20111003
LR  - 20211020
IS  - 1095-9327 (Electronic)
IS  - 1044-7431 (Print)
IS  - 1044-7431 (Linking)
VI  - 47
IP  - 2
DP  - 2011 Jun
TI  - Site-specific hyperphosphorylation of pRb in HIV-induced neurotoxicity.
PG  - 154-65
LID - 10.1016/j.mcn.2011.04.001 [doi]
AB  - HIV-Associated Neurocognitive Disorder (HAND) remains a serious complication of 
      HIV infection, despite combined Anti-Retroviral Therapy (cART). Neuronal 
      dysfunction and death are attributed to soluble factors released from activated 
      and/or HIV-infected macrophages. Most of these factors affect the cell cycle 
      machinery, determining cellular outcomes even in the absence of cell division. 
      One of the earliest events in cell cycle activation is hyperphosphorylation of 
      the retinoblastoma protein, pRb (ppRb). We and others have previously shown 
      increased ppRb expression in the CNS of patients with HIV encephalitis (HIVE) and 
      in neurons in an in vitro model of HIV-induced neurodegeneration. However, 
      trophic factors also lead to an increase in neuronal ppRb with an absence of cell 
      death, suggesting that, depending on the stimulus, hyperphosphorylation of pRb 
      can have different outcomes on neuronal fate. pRb has multiple serines and 
      threonines targeted for phosphorylation by distinct kinases, and we hypothesized 
      that different stimuli may target separate sites for phosphorylation. Thus, to 
      determine whether pRb is differentially phosphorylated in response to different 
      stimuli and whether any of these sites is preferentially phosphorylated in 
      association with HIV-induced neurotoxicity, we treated primary rat mixed cortical 
      cultures with trophic factors, BDNF or RANTES, or with the neurotoxic factor, 
      N-methyl-d-aspartate (NMDA), or with supernatants containing factors secreted by 
      HIV-infected monocyte-derived macrophages (HIV-MDM), our in vitro model of 
      HIV-induced neurodegeneration. We found that, while BDNF and RANTES 
      phosphorylated serine807/811 and serine608 in vitro, treatment with HIV-MDM did 
      not, even though these trophic factors are components of HIV-MDM. Rather, HIV-MDM 
      targets a specific phosphorylation site, serine795, of pRb for phosphorylation in 
      vitro and this ppRb isoform is also increased in HIV-infected brains in vivo. 
      Further, overexpression of a nonphosphorylatable pRb (ppRb S795A) attenuated 
      HIV-MDM-induced neurotoxicity. These findings indicate that HIV-infection in the 
      brain is associated with site-specific hyperphosphorylation of pRb at serine795, 
      which is not induced by other tested stimuli, and that this phosphorylation 
      contributes to neuronal death in this disease, demonstrating that specific pRb 
      sites are differentially targeted and may have diverse impacts on the viability 
      of post-mitotic neurons.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - Akay, C
AU  - Akay C
AD  - Department of Pathology, School of Dental Medicine, University of Pennsylvania, 
      Philadelphia, PA 19104, USA.
FAU - Lindl, K A
AU  - Lindl KA
FAU - Wang, Y
AU  - Wang Y
FAU - White, M G
AU  - White MG
FAU - Isaacman-Beck, J
AU  - Isaacman-Beck J
FAU - Kolson, D L
AU  - Kolson DL
FAU - Jordan-Sciutto, K L
AU  - Jordan-Sciutto KL
LA  - eng
GR  - N01MH32002/MH/NIMH NIH HHS/United States
GR  - NS41202/NS/NINDS NIH HHS/United States
GR  - NS043994/NS/NINDS NIH HHS/United States
GR  - R01 NS043994-07/NS/NINDS NIH HHS/United States
GR  - R01 NS041202-09A1/NS/NINDS NIH HHS/United States
GR  - R01 NS043994/NS/NINDS NIH HHS/United States
GR  - R01 NS041202-05A1/NS/NINDS NIH HHS/United States
GR  - T32 AI007632-06/AI/NIAID NIH HHS/United States
GR  - T32 AI007632/AI/NIAID NIH HHS/United States
GR  - R01 NS041202/NS/NINDS NIH HHS/United States
GR  - T32AI-07632-06/AI/NIAID NIH HHS/United States
GR  - R01 NS043994-08/NS/NINDS NIH HHS/United States
GR  - R01 NS041202-04S1/NS/NINDS NIH HHS/United States
GR  - R01 NS041202-08/NS/NINDS NIH HHS/United States
GR  - R01 NS041202-06/NS/NINDS NIH HHS/United States
GR  - R01 NS041202-07S1/NS/NINDS NIH HHS/United States
GR  - U01 MH083545/MH/NIMH NIH HHS/United States
GR  - R01 NS041202-07/NS/NINDS NIH HHS/United States
GR  - R01 NS043994-06/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110412
PL  - United States
TA  - Mol Cell Neurosci
JT  - Molecular and cellular neurosciences
JID - 9100095
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Chemokine CCL5)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Retinoblastoma Protein)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.11.1 (Cyclin-Dependent Kinase 5)
SB  - IM
MH  - AIDS Dementia Complex/*metabolism
MH  - Adult
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Cell Death/physiology
MH  - Cells, Cultured
MH  - Chemokine CCL5/metabolism
MH  - Cyclin-Dependent Kinase 5/metabolism
MH  - HIV Infections/complications
MH  - HIV-1/*metabolism
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/metabolism
MH  - Macrophages/cytology/metabolism
MH  - Male
MH  - Middle Aged
MH  - Neuroglia/cytology/metabolism
MH  - Neurons/cytology/physiology
MH  - Phosphorylation
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Retinoblastoma Protein/*metabolism
MH  - Serine/metabolism
PMC - PMC3098915
MID - NIHMS292233
EDAT- 2011/04/21 06:00
MHDA- 2011/10/04 06:00
PMCR- 2012/06/01
CRDT- 2011/04/21 06:00
PHST- 2011/01/06 00:00 [received]
PHST- 2011/03/25 00:00 [revised]
PHST- 2011/04/04 00:00 [accepted]
PHST- 2011/04/21 06:00 [entrez]
PHST- 2011/04/21 06:00 [pubmed]
PHST- 2011/10/04 06:00 [medline]
PHST- 2012/06/01 00:00 [pmc-release]
AID - S1044-7431(11)00074-1 [pii]
AID - 10.1016/j.mcn.2011.04.001 [doi]
PST - ppublish
SO  - Mol Cell Neurosci. 2011 Jun;47(2):154-65. doi: 10.1016/j.mcn.2011.04.001. Epub 
      2011 Apr 12.