Transcript Interaction between calmodulin and ER

Functional interactions
between calmodulin and
estrogen receptor-α
逄雷制作
Introduction
◇ Estrogen receptor signalling
◆
Genomic effects
◆
Nongenomic effects
Classical
Non-classical
Ca2+
MAPK/ERK
PI3K/PKB(Akt)
NO
Introduction
◇Estrogen receptor signalling
Introduction
◇ Estrogen receptor signalling
The complexity of ER function is further
increased by the existence of cross-talk
between the nongenomic and genomic ER
signalling pathways.
Introduction
◇ Ca2+/calmodulin signalling
insulin receptor
epidermal growth factor receptor
angiotensin II receptor
G protein-coupled receptors
Introduction
◇ Ca2+/calmodulin signalling
A large body of data supports a
fundamental role for calmodulin in
cell proliferation and cell cycle progression.
Calmodulin and ER
◇Interaction between calmodulin and ER
(i) Calmodulin concentrations are increased
in malignant human mammary tissue
(ii) Ca2+/calmodulin stimulates E2 binding to ER
(iii) Calmodulin binds to ER in a Ca2+-dependent
manner and this increases the Kd of E2 binding
Calmodulin and ER
◇Interaction between calmodulin and ER
(iv) Ca2+/calmodulin stimulates tyrosine
phosphorylation and activation of ER
(v) association of calmodulin with activated
estrogen-ER complex increases the interaction
of the complex with ERE
(vi) calmodulin is required for the formation of the
ER-ERE complex and for activation of an
estrogen responsive promotor
Calmodulin and ER
◇Interaction between calmodulin and ER
(i)
(ii)
(iii)
(iv)
(v)
(vi)
★ Ca2+/calmodulin may
participate in ER-induced
transcriptional activation
and the mitogenic effects
of estrogen.
Calmodulin and ER
◇ Interaction between calmodulin and ER
E2 administration to ovariectomized
mice up-regulated,independently of ER,
by 4.5-fold the expression of calmodulin
mRNA in the uterus.
Calmodulin and ER
◇ Interaction between calmodulin and ER
Calmodulin has been shown to interact
with ER both in vitro and in cells.
◆ Binding is specific for ERα, with no association detected between calmodulin and
ERβ.
◆E2 treatment has no significant effect on the
interaction.
◆
Calmodulin and ER
◇Calmodulin modulates degradation of ERα
◆
◆
Incubation with the calmodulin antagonists dramatically decreased the amount of ERα in MCF-7
cell lysates,with essentially no ER protein detected
after 16 h incubationwith CGS9343B.
Neither CGS9343B nor trifluoperazine alters the
amount of ERα mRNA .
★Calmodulin
stabilizes ERα by reducing its
degradation.
Calmodulin and ER
◇Ca2+ and calmodulin are necessary for E2stimulated transcriptional activity of ERα
◆
◆
Incubation of cells with the calmodulin antagonist
CGS9343B completely eliminated the ability of E2
to stimulate ERα transcriptional activation.
Incubating MCF-7 cells with the cell-permeable Ca2+
chelator BAPTA-AM abrogated E2-induced ERα
transcriptional activation.
Putative mechanism of calmodulin in
ERα function
A. the interaction of ERα with calmodulin (CaM) and
transcriptional coactivators. This complex activates
transcription of ERα target genes.
Putative mechanism of calmodulin in
ERα function
B.In the absence of calmodulin the conformation of ERα is
altered, facilitating its association with corepressors and
blocking interaction with coactivators. Gene transcription is
thus inhibited.
Putative mechanism of calmodulin in
ERα function
A. At normal
intracellular
calmodulin
concentrations,
E2 induces both
transcriptional
activation and
degradation of
ERα.
Putative mechanism of calmodulin in
ERα function
B. When calmodulin
is over expressed,
as occurs in breast
carcinoma, ERα
degradation is
reduced. The
increase in the
amount of ERα
results in an
enhancement of the
growth-promoting
effects of E2.
Conclusion
◆
Calmodulin antagonists inhibit the growth of
breast cell lines and augment antiestrogen
therapy.
★ The molecular interaction between calmodulin
and ERα could be a potential target for novel
therapeutic interventions in patients with breast
cancer.
The end