PMID- 19318494
OWN - NLM
STAT- MEDLINE
DCOM- 20090604
LR  - 20191210
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 15
IP  - 8
DP  - 2009 Apr 15
TI  - Transcriptional activation of the mixed lineage leukemia-p27Kip1 pathway by a 
      somatostatin analogue.
PG  - 2620-9
LID - 10.1158/1078-0432.CCR-08-2473 [doi]
AB  - PURPOSE: Mixed lineage leukemia (MLL) is a histone methyltransferase that 
      activates gene transcription and associates with menin. In multiple endocrine 
      neoplasia type 1 (Men1), a mutation of menin caused decreased expression of the 
      p27(Kip1) and p18(Ink4C) genes and deregulated cell growth. We hypothesized that 
      the same pathway might be involved in sporadic pituitary adenomas. EXPERIMENTAL 
      DESIGN: mRNA levels for MLL, Men1, p27(Kip1), and p18(Ink4C) were measured in 
      specimens of several sporadic pituitary adenomas, and a search for clinical 
      parameters revealed that octreotide treatment affected the level of expression of 
      some genes tested. To study molecular mechanisms, we cloned and characterized the 
      MLL promoter region and used small interfering RNA for MLL and specific 
      inhibitors for signal transduction pathways. RESULTS: A strong correlation 
      between MLL and p27(Kip1) mRNA levels was observed in prolactinomas and growth 
      hormone-secreting adenomas, and these levels were attenuated except in growth 
      hormone-secreting adenomas treated with a somatostatin analogue, octreotide. 
      Conversely, the patients treated with octreotide showed high levels of 
      MLL-p27(Kip1) mRNA. Experiments in vitro showed that octreotide increased MLL and 
      p27(Kip1) protein and mRNA levels, and overexpression of MLL induced a marked 
      increase in p27(Kip1)promoter activity. Furthermore, octreotide stimulated the 
      promoter activity of the MLL gene through phosphatidylinositol 3-kinase/Akt and 
      mitogen-activated protein kinase pathways. In addition, incubation with an 
      inhibitor for methyltransferase, MTA, and knockdown of MLL completely inhibited 
      the octreotide-induced expression of p27(Kip1). CONCLUSIONS: The MLL-p27(Kip1) 
      pathway was down-regulated in the pituitary adenomas, and octreotide increased 
      the p27(Kip1) level, at least in part, by sequential transcriptional stimulation 
      of the MLL and p27(Kip1) genes through phosphatidylinositol 3-kinase/Akt and 
      mitogen-activated protein kinase pathways.
FAU - Horiguchi, Kazuhiko
AU  - Horiguchi K
AD  - Department of Medicine and Molecular Science, Gunma University Graduate School of 
      Medicine, Maebashi, Japan.
FAU - Yamada, Masanobu
AU  - Yamada M
FAU - Satoh, Tetsurou
AU  - Satoh T
FAU - Hashimoto, Koshi
AU  - Hashimoto K
FAU - Hirato, Junko
AU  - Hirato J
FAU - Tosaka, Masahiko
AU  - Tosaka M
FAU - Yamada, Shozo
AU  - Yamada S
FAU - Mori, Masatomo
AU  - Mori M
LA  - eng
PT  - Journal Article
DEP - 20090324
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Androstadienes)
RN  - 0 (Antineoplastic Agents, Hormonal)
RN  - 0 (CDKN1B protein, human)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p18)
RN  - 0 (Flavonoids)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (KMT2A protein, human)
RN  - 0 (MEN1 protein, human)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27)
RN  - 149025-06-9 (Myeloid-Lymphoid Leukemia Protein)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - RWM8CCW8GP (Octreotide)
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Adult
MH  - Androstadienes/pharmacology
MH  - Antineoplastic Agents, Hormonal/*pharmacology
MH  - Base Sequence
MH  - Cell Line, Tumor
MH  - Cyclin-Dependent Kinase Inhibitor p18/metabolism
MH  - Cyclin-Dependent Kinase Inhibitor p27
MH  - Endocrine Gland Neoplasms/*metabolism/pathology
MH  - Female
MH  - Flavonoids/pharmacology
MH  - Gene Knockdown Techniques
MH  - Histone-Lysine N-Methyltransferase
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/*genetics
MH  - Male
MH  - Middle Aged
MH  - Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism
MH  - Molecular Sequence Data
MH  - Myeloid-Lymphoid Leukemia Protein/*genetics
MH  - Octreotide/*pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Pituitary Neoplasms/*metabolism/pathology
MH  - Promoter Regions, Genetic/drug effects
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolism
MH  - RNA, Messenger/drug effects/metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Signal Transduction
MH  - Transcriptional Activation/*drug effects
MH  - Wortmannin
EDAT- 2009/03/26 09:00
MHDA- 2009/06/06 09:00
CRDT- 2009/03/26 09:00
PHST- 2009/03/26 09:00 [entrez]
PHST- 2009/03/26 09:00 [pubmed]
PHST- 2009/06/06 09:00 [medline]
AID - 1078-0432.CCR-08-2473 [pii]
AID - 10.1158/1078-0432.CCR-08-2473 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2009 Apr 15;15(8):2620-9. doi: 10.1158/1078-0432.CCR-08-2473. 
      Epub 2009 Mar 24.