PMID- 28626016
OWN - NLM
STAT- MEDLINE
DCOM- 20170822
LR  - 20211204
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 37
IP  - 30
DP  - 2017 Jul 26
TI  - The mTOR Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon 
      Regeneration and a Potential Drug Target for Central Nervous System Injury.
PG  - 7079-7095
LID - 10.1523/JNEUROSCI.0931-17.2017 [doi]
AB  - The mammalian target of rapamycin (mTOR) positively regulates axon growth in the 
      mammalian central nervous system (CNS). Although axon regeneration and functional 
      recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, 
      a negative regulator of mTOR, increases mTOR activity and induces robust axon 
      growth and regeneration. It has been suggested that inhibition of S6 kinase 1 
      (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR's 
      positive effect on axon growth. In contrast to this expectation, we demonstrate 
      that inhibition of S6K1 in CNS neurons promotes neurite outgrowth in vitro by 
      twofold to threefold. Biochemical analysis revealed that an mTOR-dependent 
      induction of PI3K signaling is involved in mediating this effect of S6K1 
      inhibition. Importantly, treating female mice in vivo with PF-4708671, a 
      selective S6K1 inhibitor, stimulated corticospinal tract regeneration across a 
      dorsal spinal hemisection between the cervical 5 and 6 cord segments (C5/C6), 
      increasing axon counts for at least 3 mm beyond the injury site at 8 weeks after 
      injury. Concomitantly, treatment with PF-4708671 produced significant locomotor 
      recovery. Pharmacological targeting of S6K1 may therefore constitute an 
      attractive strategy for promoting axon regeneration following CNS injury, 
      especially given that S6K1 inhibitors are being assessed in clinical trials for 
      nononcological indications.SIGNIFICANCE STATEMENT Despite mTOR's well-established 
      function in promoting axon regeneration, the role of its downstream target, S6 
      kinase 1 (S6K1), has been unclear. We used cellular assays with primary neurons 
      to demonstrate that S6K1 is a negative regulator of neurite outgrowth, and a 
      spinal cord injury model to show that it is a viable pharmacological target for 
      inducing axon regeneration. We provide mechanistic evidence that S6K1's negative 
      feedback to PI3K signaling is involved in axon growth inhibition, and show that 
      phosphorylation of S6K1 is a more appropriate regeneration indicator than is S6 
      phosphorylation.
CI  - Copyright (c) 2017 the authors 0270-6474/17/377079-17$15.00/0.
FAU - Al-Ali, Hassan
AU  - Al-Ali H
AUID- ORCID: 0000-0002-8899-3443
AD  - Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 
      Miami, Florida 33136.
AD  - Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller 
      School of Medicine, Miami, Florida 33136.
AD  - Department of Neurological Surgery, University of Miami Miller School of 
      Medicine, Miami, Florida 33136.
FAU - Ding, Ying
AU  - Ding Y
AD  - Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research 
      Institute, Department of Neurological Surgery, Indiana University School of 
      Medicine, Indianapolis, Indiana 46202.
AD  - Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen 
      University, Guangzhou, Guangdong 510080, China, and.
FAU - Slepak, Tatiana
AU  - Slepak T
AD  - Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 
      Miami, Florida 33136.
FAU - Wu, Wei
AU  - Wu W
AUID- ORCID: 0000-0002-7835-4963
AD  - Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research 
      Institute, Department of Neurological Surgery, Indiana University School of 
      Medicine, Indianapolis, Indiana 46202.
FAU - Sun, Yan
AU  - Sun Y
AD  - Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research 
      Institute, Department of Neurological Surgery, Indiana University School of 
      Medicine, Indianapolis, Indiana 46202.
AD  - Department of Anatomy, Histology and Embryology, School of Basic Medical 
      Sciences, Fudan University, Shanghai, 200032, China.
FAU - Martinez, Yania
AU  - Martinez Y
AD  - Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 
      Miami, Florida 33136.
FAU - Xu, Xiao-Ming
AU  - Xu XM
AD  - Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research 
      Institute, Department of Neurological Surgery, Indiana University School of 
      Medicine, Indianapolis, Indiana 46202.
FAU - Lemmon, Vance P
AU  - Lemmon VP
AD  - Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 
      Miami, Florida 33136, jbixby@med.miami.edu vlemmon@med.miami.edu.
AD  - Department of Neurological Surgery, University of Miami Miller School of 
      Medicine, Miami, Florida 33136.
FAU - Bixby, John L
AU  - Bixby JL
AUID- ORCID: 0000-0003-1633-5318
AD  - Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 
      Miami, Florida 33136, jbixby@med.miami.edu vlemmon@med.miami.edu.
AD  - Department of Neurological Surgery, University of Miami Miller School of 
      Medicine, Miami, Florida 33136.
AD  - Department of Molecular and Cellular Pharmacology, University of Miami Miller 
      School of Medicine, Miami, Florida 33136.
LA  - eng
GR  - I01 BX002356/BX/BLRD VA/United States
GR  - R01 HD057632/HD/NICHD NIH HHS/United States
GR  - R01 NS059622/NS/NINDS NIH HHS/United States
GR  - R01 NS100531/NS/NINDS NIH HHS/United States
PT  - Journal Article
DEP - 20170616
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Imidazoles)
RN  - 0 (PF-4708671)
RN  - 0 (Piperazines)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
RN  - EC 2.7.11.1 (Rps6ka1 protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Axons/*metabolism
MH  - Cells, Cultured
MH  - Drug Delivery Systems
MH  - Gene Expression Regulation, Enzymologic/physiology
MH  - Imidazoles/*administration & dosage
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Molecular Targeted Therapy
MH  - Neuronal Outgrowth/drug effects
MH  - Piperazines/*administration & dosage
MH  - Protein Binding
MH  - Ribosomal Protein S6 Kinases, 90-kDa/antagonists & inhibitors/*metabolism
MH  - Spinal Cord Injuries/*drug therapy/*enzymology
MH  - Spinal Cord Regeneration/*drug effects
MH  - Substrate Specificity
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Treatment Outcome
PMC - PMC5546395
OTO - NOTNLM
OT  - S6K
OT  - axon regeneration
OT  - drug discovery
OT  - drug target
OT  - kinase
OT  - spinal cord injury
COIS- The authors declare no competing financial interests.
EDAT- 2017/06/20 06:00
MHDA- 2017/08/23 06:00
PMCR- 2018/01/26
CRDT- 2017/06/20 06:00
PHST- 2017/04/04 00:00 [received]
PHST- 2017/05/18 00:00 [revised]
PHST- 2017/05/27 00:00 [accepted]
PHST- 2017/06/20 06:00 [pubmed]
PHST- 2017/08/23 06:00 [medline]
PHST- 2017/06/20 06:00 [entrez]
PHST- 2018/01/26 00:00 [pmc-release]
AID - JNEUROSCI.0931-17.2017 [pii]
AID - 0931-17 [pii]
AID - 10.1523/JNEUROSCI.0931-17.2017 [doi]
PST - ppublish
SO  - J Neurosci. 2017 Jul 26;37(30):7079-7095. doi: 10.1523/JNEUROSCI.0931-17.2017. 
      Epub 2017 Jun 16.