Lung
cancer
Neuroendocrine disease
2007/11/3/32
Mol Cell
Biol. 2007 Feb;27(4):1495-504. Epub
2006 Dec 4. Bai F, Pei XH, Nishikawa
T, Smith
MD, Xiong Y. Lineberger
Comprehensive Cancer Center, Department of Biochemistry and Biophysics,
University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295,
USA. Mutant mice lacking both cyclin-dependent kinase (CDK)
inhibitors p18(Ink4c) and p27(Kip1) develop a
tumor spectrum reminiscent of human multiple endocrine neoplasia
(MEN) syndromes. To determine how p18 and p27 genetically interact with
Men1, the tumor suppressor gene mutated in familial MEN1, we characterized
p18-Men1 and p27-Men1 double mutant mice. Compared with their corresponding
single mutant littermates, the p18(-/-); Men1(+/-)
mice develop tumors at an accelerated rate and with an increased incidence
in the pituitary, thyroid, parathyroid, and pancreas. In the pituitary and
pancreatic islets, phosphorylation of the
retinoblastoma (Rb) protein at both CDK2 and
CDK4/6 sites was increased in p18(-/-) and
Men1(+/-) cells and was further increased in p18(-/-); Men1(+/-) cells. The
remaining wild-type Men1 allele was lost in most tumors from Men1(+/-) mice but was retained in most tumors from
p18(-/-); Men1(+/-) mice. Combined mutations of p27(-/-)
and Men1(+/-), in contrast, did not exhibit noticeable synergistic
stimulation of Rb kinase
activity, cell proliferation, and tumor growth. These results demonstrate
that functional collaboration exists between p18 and Men1 and suggest that
Men1 may regulate additional factor(s) that interact with p18 and p27
differently. PMID: 17145768 [PubMed
- indexed for MEDLINE] Cancer Res.
2006 May 1;66(9):4929-35. Dreijerink KM, Mulder KW, Winkler
GS, Höppener JW, Lips
CJ, Timmers HT. Departments
of Physiological Chemistry, The product of the multiple
endocrine neoplasia type 1 (MEN1) tumor
suppressor gene, menin, is an integral component
of MLL1/MLL2 histone methyltransferase
complexes specific for Lys4 of histone H3 (H3K4).
We show that menin is a transcriptional coactivator of the nuclear receptors for estrogen and
vitamin D. Activation of the endogenous estrogen-responsive TFF1 (pS2) gene
results in promoter recruitment of menin and in
elevated trimethylation of H3K4. Knockdown of menin reduces both activated TFF1 (pS2) transcription
and H3K4 trimethylation. In addition, menin can directly interact with the estrogen
receptor-alpha (ERalpha) in a hormone-dependent
manner. The majority of disease-related MEN1 mutations prevent menin-ERalpha interaction. Importantly, ERalpha-interacting mutants are also defective in coactivator function. Our results indicate that menin is a critical link between recruitment of histone methyltransferase
complexes and nuclear receptor-mediated transcription. PMID: 16651450 [PubMed
- indexed for MEDLINE] Chen
YX, Yan J, Keeshan K, Tubbs
AT, Wang
H, Silva
A, Brown
EJ, Hess
JL, Pear
WS, Hua X. Abramson Family Cancer
Research Institute, Department of Cancer Biology, Abramson Cancer Center,
University of Pennsylvania, Philadelphia, PA 19104-6160, USA. Menin
is the product of the tumor suppressor gene Men1 that is mutated in the
inherited tumor syndrome multiple endocrine neoplasia
type 1 (MEN1). Menin has been shown to interact
with SET-1 domain-containing histone 3 lysine 4
(H3K4) methyltransferases including mixed lineage
leukemia proteins to regulate homeobox (Hox) gene expression in vitro. Using conditional Men1
knockout mice, we have investigated the requirement for menin
in hematopoiesis and myeloid transformation. Men1
excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white
blood cell count. Menin directly activates Hoxa9
expression, at least in part, by binding to the Hoxa9 locus, facilitating methylation of H3K4, and recruiting the methylated H3K4 binding protein chd1 to the locus.
Consistent with signaling downstream of menin, ectopic expression of both Hoxa9 and Meis1 rescues
colony formation defects in Men1-excised bone marrow. Moreover, Men1
excision also suppresses proliferation of leukemogenic
mixed lineage leukemia-AF9 fusion-protein-transformed myeloid cells and
Hoxa9 expression. These studies uncover an important role for menin in both normal hematopoiesis
and myeloid transformation and provide a mechanistic understanding of menin's function in these processes that may be used
for therapy. PMID: 16415155 [PubMed
- indexed for MEDLINE]
p18Ink4c, but not p27Kip1, collaborates with
Men1 to suppress neuroendocrine organ tumors.
Menin links estrogen
receptor activation to histone H3K4 trimethylation.
The tumor suppressor menin
regulates hematopoiesis and myeloid
transformation by influencing Hox gene
expression.