PMID- 22791749
OWN - NLM
STAT- MEDLINE
DCOM- 20130621
LR  - 20211203
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 21
IP  - 20
DP  - 2012 Oct 15
TI  - Altered LKB1/AMPK/TSC1/TSC2/mTOR signaling causes disruption of Sertoli cell 
      polarity and spermatogenesis.
PG  - 4394-405
AB  - Male patients with Peutz-Jeghers syndrome (PJS) have defective spermatogenesis 
      and are at increased risk of developing Sertoli cell tumors. Mutations in the 
      Liver Kinase B1 (LKB1/STK11) gene are associated with the pathogenesis of PJS and 
      have been identified in non-PJS patients with sporadic testicular cancers. The 
      mechanisms controlled by LKB1 signaling in Sertoli cell functions and testicular 
      biology have not been described. We have conditionally deleted the Lkb1 gene 
      (Lkb1(cko)) in somatic testicular cells to define the molecular mechanisms 
      involved in the development of the testicular phenotype observed in PJS patients. 
      Focal vacuolization in some of the seminiferous tubules was observed in 
      4-week-old mutant testes but germ cell development appeared to be normal. 
      However, similar to PJS patients, we observed progressive germ cell loss and 
      Sertoli cell only tubules in Lkb1(cko) testes from mice older than 10 weeks, 
      accompanied by defects in Sertoli cell polarity and testicular junctional 
      complexes and decreased activation of the MAP/microtubule affinity regulating and 
      focal adhesion kinases. Suppression of AMP kinase and activation of mammalian 
      target of rapamycin (mTOR) signaling were also observed in Lkb1(cko) testes. Loss 
      of Tsc1 or Tsc2 copies the progressive Lkb1(cko) phenotype, suggesting that 
      dysregulated activation of mTOR contributes to the pathogenesis of the Lkb1(cko) 
      testicular phenotype. Pten(cko) mice had a normal testicular phenotype, which 
      could be explained by the comparative lack of mTOR activation detected. These 
      studies describe the importance of LKB1 signaling in testicular biology and the 
      possible molecular mechanisms driving the pathogenesis of the testicular defects 
      observed in PJS patients.
FAU - Tanwar, Pradeep S
AU  - Tanwar PS
AD  - Vincent Center For Reproductive Biology/Thier 931, Department of Obstetrics, 
      Gynecology and Reproductive Biology, Massachusetts General Hospital and Harvard 
      Medical School, Boston, MA 02114, USA.
FAU - Kaneko-Tarui, Tomoko
AU  - Kaneko-Tarui T
FAU - Zhang, LiHua
AU  - Zhang L
FAU - Teixeira, Jose M
AU  - Teixeira JM
LA  - eng
GR  - R01 HD052701/HD/NICHD NIH HHS/United States
GR  - HD052701/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120712
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (AMPK alpha1 subunit, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Stk11 protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/*genetics/metabolism
MH  - Animals
MH  - Cell Polarity/*genetics
MH  - Male
MH  - Mice
MH  - Protein Serine-Threonine Kinases/*genetics/metabolism
MH  - Sertoli Cells/*metabolism
MH  - *Signal Transduction
MH  - Spermatogenesis/*genetics
MH  - TOR Serine-Threonine Kinases/*genetics/metabolism
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tumor Suppressor Proteins/*genetics/metabolism
PMC - PMC3459463
EDAT- 2012/07/14 06:00
MHDA- 2013/06/25 06:00
PMCR- 2013/10/15
CRDT- 2012/07/14 06:00
PHST- 2012/07/14 06:00 [entrez]
PHST- 2012/07/14 06:00 [pubmed]
PHST- 2013/06/25 06:00 [medline]
PHST- 2013/10/15 00:00 [pmc-release]
AID - dds272 [pii]
AID - 10.1093/hmg/dds272 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2012 Oct 15;21(20):4394-405. doi: 10.1093/hmg/dds272. Epub 2012 
      Jul 12.