Breast cancer
2008/4/6/37
Mol Endocrinol.
2008 Mar;22(3):559-69. Epub
2007 Dec 20. UCLA-Orthopaedic Hospital Department of Orthopaedic
Surgery, New World primates exhibit a form of
resistance to estrogens that is associated with overexpression
of an estrogen response element (ERE)-binding protein (ERE-BP) and an
intracellular estradiol (E(2))-binding protein
(IEBP). Both proteins suppress E(2)-mediated
transcription when overexpressed in estrogen
receptor-alpha (ERalpha)-positive cells. Although
ERE-BP acts as a competitor for ERE occupancy by liganded
ERalpha, the function of IEBP and its human
homolog, heat-shock protein 27 (hsp27), is less clear. In data presented
here, we have used E(2)-responsive human MCF-7 breast cancer cells to show
that IEBP/hsp27 can regulate estrogen signaling as a cytosolic
decoy for E(2) and as a protein chaperone for ERalpha.
Furthermore, co-immunoprecipitation, colocalization, yeast two-hybrid, and glutathione S-transferase pull-down analyses indicate that IEBP/hsp27
also interacts with ERE-BP to form a dynamic complex that appears to cycle
between the cytoplasm and nucleus during normal estrogen signaling. Overexpression of either IEBP/hsp27 or ERE-BP in MCF-7
cells resulted in abnormal subcellular
distribution of the IEBP/hsp27 and ERE-BP, with concomitant dysregulation of ERE occupancy as determined by
chromatin immunoprecipitation. We hypothesize
that IEBP/hsp27 and ERE-BP not only cause hormone resistance in Cheskis BJ, Greger J, Cooch N, McNally
C, McLarney S, Lam
HS, Rutledge
S, Mekonnen B, Hauze D, Nagpal S, Freedman
LP. Department
of Women's Health and Musculoskeletal Biology, Wyeth
Research, Estrogens play a critical role in the regulation of
cellular proliferation, differentiation, and apoptosis. Evidence indicates
that this regulation is mediated by a complex interface of direct control
of gene expression (so-called "genomic action") and by regulation
of cell-signaling/phosphorylation cascades
(referred to as the "non-genomic", or "extranuclear"
action). However, the mechanisms of the non-genomic action of estrogens are
not well defined. We have recently described the identification of a novel
scaffold protein termed MNAR (modulator of non-genomic action of estrogen
receptor), that couples conventional steroid receptors with extranuclear signal transduction pathways, thus
potentially providing additional and tissue- or cell-specific level of
steroid hormone regulation of cell functions. We have demonstrated that the
MNAR is required for ER alpha (ERa) interaction
with p60(src) (Src), which leads to activation of Src/MAPK
pathway. Our new data also suggest that activation of cSrc
in response to E2 leads to MNAR phosphorylation,
interaction with p85, and activation of the PI3 and Akt
kinases. These data therefore suggest that MNAR
acts as an important scaffold that integrates ERa
action in regulation of important signaling pathways. ERa
non-genomic action has Wang
C, Bomberg E, Billington C, Levine
A, Kotz CM. Recent studies show that
brain-derived neurotrophic factor (BDNF)
decreases feeding and body weight after peripheral and ventricular
administration. BDNF mRNA and protein, and its receptor tyrosine kinase B (TrkB) are widely distributed
in the hypothalamus and other brain regions. However, there are few reports
on specific brain sites of actions for BDNF. We evaluated the effect of
BDNF in the hypothalamic paraventricular nucleus
(PVN) on feeding. BDNF injected unilaterally or bilaterally into the PVN of
food-deprived and nondeprived rats significantly
decreased feeding and body weight gain within the 0- to 24-h and 24- to
48-h postinjection intervals. Effective doses
producing inhibition of feeding behavior did not establish a conditioned
taste aversion. PVN BDNF significantly decreased PVN neuropeptide
Y (NPY)-induced feeding at 1, 2, and 4 h following injection. BDNF
administration in the PVN abolished food-restriction-induced NPY gene
expression in the hypothalamic arcuate nucleus.
In conclusion, BDNF in the PVN significantly decreases food intake and body
weight gain, suggesting that the PVN is an important site of action for
BDNF in its effects on energy metabolism. Furthermore, BDNF appears to
interact with NPY in its anorectic actions, although a direct effect on NPY
remains to be established. PMID: 17581841 [PubMed
- in process]] Mol Psychiatry. 2005 Oct;10(10):939-43. Association
of the paternally transmitted copy of common Valine
allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to
ADHD. Kent L, Green E, Hawi
Z, Kirley
A, Dudbridge
F, Lowe N, Raybould
R, Langley K,
Bray N, Fitzgerald M,
Owen MJ, O'Donovan MC,
Gill M, Thapar
A, Craddock N.
Developmental Psychiatry, Attention deficit hyperactivity disorder (ADHD) is a
common, highly heritable, neurodevelopmental
disorder with onset in early childhood. Genes involved in neuronal
development and growth are, thus, important etiological candidates and
brain-derived neurotrophic factor (BDNF), has
been hypothesized to play a role in the pathogenesis of ADHD. BDNF is a
member of the neurotrophin family and is involved
in the survival and differentiation of dopaminergic
neurons in the developing brain (of relevance because drugs that block the
dopamine transporter can be effective therapeutically). The common Val66Met
functional polymorphism in the human BDNF gene (rs
6265) was genotyped in a collaborative family-based sample of 341 white PMID: 15940292 [PubMed -
indexed for MEDLINE Dev Biol.
2003 Nov 15;263(2):216-30. Jourdi H, Iwakura Y, Narisawa-Saito M, Ibaraki
K, Xiong H, Watanabe
M, Hayashi
Y, Takei
N, Nawa H. Department
of Molecular Neurobiology, Brain Research Institute, Postsynaptic molecules with PDZ
domains (PDZ proteins) interact with various glutamate receptors and
regulate their subcellular trafficking and
stability. In rat neocortical development, the protein expression of
AMPA-type glutamate receptor GluR1 lagged behind its mRNA expression and
rather paralleled an increase in PDZ protein levels. One of the neurotrophins, brain-derived neurotrophic
factor (BDNF), appeared to contribute to this process, regulating the PDZ
protein expression. In neocortical cultures, BDNF
treatment upregulated SAP97, GRIP1, and Pick1 PDZ
proteins. Conversely, BDNF gene targeting downregulated these same PDZ molecules. The
BDNF-triggered increases in PDZ proteins resulted in the elevation of their
total association with the AMPA receptors GluR1 and GluR2/3, which led to
the increase in AMPA receptor proteins. When Sindbis
viruses carrying GluR1 or GluR2 C-terminal decoys disrupted their
interactions, GluR2 C-terminal decoys inhibited both BDNF-triggered GluR1
and GluR2/3 increases, whereas GluR1 C-terminal decoys blocked only the
BDNF-triggered GluR1 increase. In agreement, coexpression
of SAP97 and GluR1 in nonneuronal HEK293 cells
increased both proteins compared with their single transfection,
implying mutual stabilization. This work reveals a novel function of BDNF
in postsynaptic development by regulating the PDZ protein expression. PMID: 14597197 [PubMed
- indexed for MEDLINE] Kaufman
J, Yang
BZ, Douglas-Palumberi H, Grasso D, Lipschitz D, Houshyar S, Krystal JH, Gelernter
J. Child and Adolescent Research
and Education Program, Department of Psychiatry, Yale University School of
Medicine, New Haven, Connecticut 06511, USA. joan.kaufman@yale.edu BACKGROUND: Child abuse and
genotype interact to contribute to risk for depression in children. This
study examined gene-by-gene and gene-by-environment interactions. METHODS:
The study included 196 children: 109 maltreated and 87 nonmaltreated
comparison subjects. Measures of psychiatric symptomatology
and social supports were obtained using standard research instruments, and
serotonin transporter (5-HTTLPR) (locus SLC6A4) and brain-derived neurotrophic factor (BDNF) (variant val66met) genotypes
were obtained from saliva-derived DNA specimens. Population structure was
controlled by means of ancestral proportion scores computed based on
genotypes of ancestry informative markers in the entire sample. RESULTS:
There was a significant three-way interaction between BDNF genotype,
5-HTTLPR, and maltreatment history in predicting depression. Children with
the met allele of the BDNF gene and two short alleles of 5-HTTLPR had the
highest depression scores, but the vulnerability associated with these two genotypes
was only evident in the maltreated children. A significant four-way
interaction also emerged, with social supports found to further moderate
risk for depression. CONCLUSIONS: To the best of our knowledge, this is the
first investigation to demonstrate a gene-by-gene interaction conveying
vulnerability to depression. The current data also show a protective effect
of social supports in ameliorating genetic and environmental risk for
psychopathology. PMID: 16458264 [PubMed
- indexed for MEDLINE]
Control of estradiol-directed gene transactivation
by an intracellular estrogen-binding protein and an estrogen response
element-binding protein.
MNAR plays an important role in ERa
activation of Src/MAPK and PI3K/Akt signaling pathways.
Brain-derived neurotrophic
factor in the hypothalamic paraventricular
nucleus reduces energy intake.
Brain-derived neurotrophic
factor signal enhances and maintains the expression of AMPA receptor-associated
PDZ proteins in developing cortical neurons.
Brain-derived neurotrophic factor-5-HTTLPR gene interactions and
environmental modifiers of depression in children.