PMID- 30285764
OWN - NLM
STAT- MEDLINE
DCOM- 20190510
LR  - 20190510
IS  - 1478-811X (Electronic)
IS  - 1478-811X (Linking)
VI  - 16
IP  - 1
DP  - 2018 Oct 1
TI  - Reduced menin expression impairs rapamycin effects as evidenced by an increase in 
      mTORC2 signaling and cell migration.
PG  - 64
LID - 10.1186/s12964-018-0278-2 [doi]
LID - 64
AB  - BACKGROUND: Mammalian target of rapamycin (mTOR) is a master regulator of various 
      cellular responses by forming two functional complexes, mTORC1 and mTORC2. mTOR 
      signaling is frequently dysregulated in pancreatic neuroendocrine tumors (PNETs). 
      mTOR inhibitors have been used in attempts to treat these lesions, and prolonged 
      progression free survival has been recorded. If this holds true also for the 
      multiple endocrine neoplasia type 1 (MEN1) associated PNETs is yet unclear. We 
      investigated the relationship between expression of the MEN1 protein menin and 
      mTOR signaling in the presence or absence of the mTOR inhibitor rapamycin. 
      METHODS: In addition to use of menin wild type and menin-null mouse embryonic 
      fibroblasts (MEFs), menin was silenced by siRNA in pancreatic neuroendocrine 
      tumor cell line BON-1. Panels of protein phosphorylation, as activation markers 
      downstream of PI3k-mTOR-Akt pathways, as well as menin expression were evaluated 
      by immunoblotting. The impact of menin expression in the presence and absence of 
      rapamycin was determinate upon Wound healing, migration and proliferation in MEFs 
      and BON1 cells. RESULTS: PDGF-BB markedly increased phosphorylation of mTORC2 
      substrate Akt, at serine 473 (S473) and threonine 450 (T450) in menin(-/-) MEFs 
      but did not alter phosphorylation of mTORC1 substrates ribosomal protein S6 or 
      eIF4B. Acute rapamycin treatment by mTORC1-S6 inhibition caused a greater 
      enhancement of Akt phosphorylation on S473 in menin(-/-) cells as compared to 
      menin(+/+) MEFs (116% vs 38%). Chronic rapamycin treatment, which inhibits both 
      mTORC1and 2, reduced Akt phosphorylation of S473 to a lesser extent in menin(-/-) 
      MEFs than menin(+/+) MEFs (25% vs 75%). Silencing of menin expression in human 
      PNET cell line (BON1) also enhanced Akt phosphorylation at S473, but not 
      activation of mTORC1. Interestingly, silencing menin in BON1 cells elevated S473 
      phosphorylation of Akt in both acute and chronic treatments with rapamycin. 
      Finally, we show that the inhibitory effect of rapamycin on serum mediated wound 
      healing and cell migration is impaired in menin(-/-) MEFs, as well as in 
      menin-silenced BON1 cells. CONCLUSIONS: Menin is involved in regulatory mechanism 
      between the two mTOR complexes, and its reduced expression is accompanied with 
      increased mTORC2-Akt signaling, which consequently impairs anti-migratory effect 
      of rapamycin.
FAU - Razmara, Masoud
AU  - Razmara M
AUID- ORCID: 0000-0002-1037-4810
AD  - Department of medical sciences, Science for Life Laboratory, Uppsala University, 
      Uppsala, Sweden. Masoud.Razmara@medsci.uu.se.
FAU - Monazzam, Azita
AU  - Monazzam A
AD  - Department of medical sciences, Science for Life Laboratory, Uppsala University, 
      Uppsala, Sweden.
FAU - Skogseid, Britt
AU  - Skogseid B
AD  - Department of medical sciences, Science for Life Laboratory, Uppsala University, 
      Uppsala, Sweden.
LA  - eng
GR  - Cancerfonden, CAN 2014/895/Swedish Cancer Society (Cancerfonden, CAN 
      2014/895)./International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181001
PL  - England
TA  - Cell Commun Signal
JT  - Cell communication and signaling : CCS
JID - 101170464
RN  - 0 (MEN1 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Gene Expression Regulation/*drug effects
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 2/*metabolism
MH  - Mice
MH  - Phosphorylation/drug effects
MH  - Proto-Oncogene Proteins/deficiency/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - RNA, Small Interfering/genetics
MH  - Signal Transduction/*drug effects
MH  - Sirolimus/*pharmacology
PMC - PMC6167842
OTO - NOTNLM
OT  - Akt
OT  - MEN1
OT  - PI3K
OT  - PNET
OT  - Rapamycin
OT  - mTOR
COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not applicable. CONSENT FOR 
      PUBLICATION: All authors approved the final manuscript. COMPETING INTERESTS: The 
      authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer 
      Nature remains neutral with regard to jurisdictional claims in published maps and 
      institutional affiliations.
EDAT- 2018/10/05 06:00
MHDA- 2019/05/11 06:00
PMCR- 2018/10/01
CRDT- 2018/10/05 06:00
PHST- 2018/07/16 00:00 [received]
PHST- 2018/09/24 00:00 [accepted]
PHST- 2018/10/05 06:00 [entrez]
PHST- 2018/10/05 06:00 [pubmed]
PHST- 2019/05/11 06:00 [medline]
PHST- 2018/10/01 00:00 [pmc-release]
AID - 10.1186/s12964-018-0278-2 [pii]
AID - 278 [pii]
AID - 10.1186/s12964-018-0278-2 [doi]
PST - epublish
SO  - Cell Commun Signal. 2018 Oct 1;16(1):64. doi: 10.1186/s12964-018-0278-2.