PMID- 21264250
OWN - NLM
STAT- MEDLINE
DCOM- 20110802
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 1
DP  - 2011 Jan 14
TI  - The menin tumor suppressor protein is phosphorylated in response to DNA damage.
PG  - e16119
LID - 10.1371/journal.pone.0016119 [doi]
LID - e16119
AB  - BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a heritable cancer 
      syndrome characterized by tumors of the pituitary, pancreas and parathyroid. 
      Menin, the product of the MEN1 gene, is a tumor suppressor protein that functions 
      in part through the regulation of transcription mediated by interactions with 
      chromatin modifying enzymes. PRINCIPAL FINDINGS: Here we show menin association 
      with the 5' regions of DNA damage response genes increases after DNA damage and 
      is correlated with RNA polymerase II association but not with changes in histone 
      methylation. Furthermore, we were able to detect significant levels of menin at 
      the 3' regions of CDKN1A and GADD45A under conditions of enhanced transcription 
      following DNA damage. We also demonstrate that menin is specifically 
      phosphorylated at Ser394 in response to several forms of DNA damage, Ser487 is 
      dynamically phosphorylated and Ser543 is constitutively phosphorylated. 
      Phosphorylation at these sites however does not influence the ability to interact 
      with histone methyltransferase activity. In contrast, the interaction between 
      menin and RNA polymerase II is influenced by phosphorylation, whereby a 
      phospho-deficient mutant had a higher affinity for the elongating form of RNA 
      polymerase compared to wild type. Additionally, a subset of MEN1-associated 
      missense point mutants, fail to undergo DNA damage dependent phosphorylation. 
      CONCLUSION: Together, our findings suggest that the menin tumor suppressor 
      protein undergoes DNA damage induced phosphorylation and participates in the DNA 
      damage transcriptional response.
FAU - Francis, Joshua
AU  - Francis J
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts, United States of America.
FAU - Lin, Wenchu
AU  - Lin W
FAU - Rozenblatt-Rosen, Orit
AU  - Rozenblatt-Rosen O
FAU - Meyerson, Matthew
AU  - Meyerson M
LA  - eng
GR  - F32 DK077424/DK/NIDDK NIH HHS/United States
GR  - F32DK77424/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110114
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (MEN1 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.7.- (RNA Polymerase II)
SB  - IM
MH  - Cell Line
MH  - DNA Damage/*genetics
MH  - Humans
MH  - Phosphorylation/physiology
MH  - Protein Binding
MH  - Proto-Oncogene Proteins/*metabolism
MH  - RNA Polymerase II/metabolism
MH  - Serine/metabolism
MH  - Transcription, Genetic
MH  - Tumor Suppressor Proteins/*metabolism
PMC - PMC3021530
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2011/01/26 06:00
MHDA- 2011/08/04 06:00
PMCR- 2011/01/14
CRDT- 2011/01/26 06:00
PHST- 2010/08/06 00:00 [received]
PHST- 2010/12/08 00:00 [accepted]
PHST- 2011/01/26 06:00 [entrez]
PHST- 2011/01/26 06:00 [pubmed]
PHST- 2011/08/04 06:00 [medline]
PHST- 2011/01/14 00:00 [pmc-release]
AID - PONE-D-10-00410 [pii]
AID - 10.1371/journal.pone.0016119 [doi]
PST - epublish
SO  - PLoS One. 2011 Jan 14;6(1):e16119. doi: 10.1371/journal.pone.0016119.