Apert Syndrome
Bone development
Gastric cancer
. Dev
Biol. 2006 Nov 15;299(2):478-88. Epub 2006 Aug 24. FGF signal transduction
and the regulation of Cdx gene expression. ·
Keenan ID,
Sharrard
RM, Isaacs HV.
Department of Biology, Cdx homeodomain
transcription factors play important roles in the development of the
vertebrate body axis and gut epithelium. Signaling involving FGF, wnt and retinoic acid ligands
has been implicated in the regulation of individual Cdx
genes. In this study we examine the requirement for FGF-dependent signal
transduction pathways in the regulation of Cdx
gene expression. In the amphibian Xenopus laevis the earliest expression of Cdx1, Cdx2 and Cdx4
is within the developing mesoderm. We show that a functional FGF signaling
pathway is required for the normal expression of all three amphibian Cdx genes during gastrula stages. We show that FGF
stimulation activates signaling through both the MAP kinase
pathway and the PI-3 kinase pathway in Xenopus tissue explants. However, our analysis of these
pathways in gastrula stage embryos indicates that the MAP kinase pathway is required for Cdx
gene expression, whereas the PI-3 kinase pathway
is not. We show that FGF and wnt signaling can
interact in the regulation of Cdx genes and
during gastrula stages the normal expression of the Cdx
genes requires the activity of both pathways. Furthermore, we show that wnt mediated Cdx regulation
is independent of the MAP kinase pathway. PMID: 16982047 [PubMed -
indexed for MEDLINE] Dev
Biol. 2006 Sep 1;297(1):14-25. Epub 2006 Apr 21. Regulated expression of
FLRT genes implies a functional role in the regulation of FGF signalling during mouse development. ·
Haines BP,
Wheldon
LM, Summerbell
D, Heath JK, Rigby PW. Section of Gene Function and Regulation, The Within the mammalian genome, there are many multimember
gene families that encode membrane proteins with extracellular
leucine rich repeats which are thought to act as
cell adhesion or signalling molecules. We
previously showed that the members of the NLRR gene family are expressed in
a developmentally restricted manner in the mouse with NLRR-1 being
expressed in the developing myotome. The FLRT
gene family shows a similar genomic layout and predicted protein secondary
structure to the NLRRs so we analysed
expression of the three FLRT genes during mouse development. FLRTs are glycosylated
membrane proteins expressed at the cell surface which localise
in a homophilic manner to cell-cell contacts
expressing the focal adhesion marker vinculin.
Each member of the FLRT family has a distinct, highly regulated expression
pattern, as was seen for the NLRR family. FLRT3 has a provocative
expression pattern during somite development
being expressed in regions of the somite where
muscle precursor cells migrate from the dermomyotome
and move into the myotome, and later in myotomal precursors destined to migrate towards their
final destination, for example, those that form the ventral body wall.
FLRT3 is also expressed at the midbrain/hindbrain boundary and in the
apical ectodermal ridge, regions where FGF signalling is known to be important, suggesting that
the role for FLRT3 in FGF signalling identified
in Xenopus is conserved in mammals. FLRT1 is
expressed at brain compartmental boundaries and FLRT2 is expressed in a
subset of the sclerotome, adjacent to the region
that forms the syndetome, suggesting that
interaction with FGF signalling may be a general
property of FLRT proteins. We confirmed this by showing that all FLRTs can interact with FGFR1 and FLRTs
can be induced by the activation of FGF signalling
by FGF-2. We conclude that FLRT proteins act as regulators of FGF signalling, being induced by the signal and then able
to interact with the signalling receptor, in many
tissues during mouse embryogenesis. This process may, in part, be dependent
on homophilic intercellular interactions between
FLRT molecules. PMID: 16872596 [PubMed -
indexed for MEDLINE] Dev Dyn. 2005 Jul;233(3):847-52. Foxc1 integrates Fgf and Bmp signalling
independently of twist or noggin during calvarial
bone development. ·
Rice R, Rice DP, Thesleff
I. Developmental Biology Programme, Calvarial bone and suture development is
under complex regulation where bone morphogenetic protein (Bmp) and
fibroblast growth factor (Fgf) signalling interact with Msx2/Twist and Noggin and
regulate frontal bone primordia proliferation and
suture fusion, respectively. We have shown previously that the winged helix
transcription factor Foxc1, which is necessary for calvarial
bone development, is required for the Bmp regulation of Msx2. We now show
that FGF2 regulates the expression of Foxc1, indicating that Foxc1
integrates Bmp and Fgf signalling
pathways. We also show that Foxc1 is not needed for the acquisition of osteogenic potential or for the differentiation of osteoblasts. The expression of Fgf
receptors and Twist were normal in Foxc1-deficient calvarial
mesenchyme, and ectopic
FGF2 was able to induce the expression Osteopontin.
Furthermore, we demonstrate that Foxc1 does not participate in the
regulation of Noggin expression. Our findings indicate that Foxc1
integrates the Bmp and Fgf signalling
pathways independently of Twist or Noggin. This signalling
network is essential for the correct patterning and growth of calvarial bones. PMID: 15906377 [PubMed -
indexed for MEDLINE] J
Recept Signal Transduct
Res. 2006;26(4):225-40. Interaction between TRPC
channel subunits in endothelial cells. ·
Antoniotti
S, Fiorio
Pla A, Barral
S, Scalabrino
O, Munaron
L, Lovisolo
D. Department of Animal and Human
Biology, Transient Receptor Potential Canonical (TRPC) proteins
have been identified in mammals as a family of plasma membrane
calcium-permeable channels activated by different kinds of stimuli in
several cell types. We have studied TRPC subunit expression in bovine
aortic endothelial (BAE-1) cells, where stimulation with basic fibroblast
growth factor (bFGF), a potent angiogenetic factor, induces calcium entry carried at
least partially by TRPC1 channels. By means of a RT-PCR approach, we have
found that, in addition to TRPC1, only TRPC4 is expressed, both at the mRNA
and protein level, as confirmed by immunoblotting
and immunocytochemical analysis. Because
functional TRPC channels are formed by assembly of four subunits in either
homo- or heterotetrameric structures, we have
carried out immunoprecipitation experiments and
showed that TRPC1 and TRPC4 interact to form heteromers
in these cells, independently from culture conditions (high or low percent
of fetal calf serum, stimulation with bFGF).
Moreover, the data show that TRPC subunits are not tyrosine-phosphorylated after bFGF
stimulation and they do not co-immunoprecipitate
with the type 1 FGF receptor. These results suggest that BAE-1 cells are a
suitable model to study function and regulation of endogenous TRPC1/TRPC4 heteromers. PMID: 16818374 [PubMed -
indexed for MEDLINE] ·
·
tion. Differential Regulation of CD40-Mediated TNF
Receptor-Associated Factor Degradation in B Lymphocytes. B Cell Maturation Antigen, the Receptor
for a Proliferation-Inducing Ligand and B Cell-Activating
Factor of the TNF Family, Induces Antigen Presentation in B Cells. ICAM-1 gene expression in endothelial cells: Effects on the
inhibition of STAT3 phosphorylation.
Moore
CR, Bishop GA.
Interdisciplinary Graduate Program in Immunology.
Engagement of CD40 on murine B cells by its ligand CD154 induces the binding of TNFR-associated
factors (TRAFs) 1, 2, 3, and 6, followed by the
rapid degradation of TRAFs 2 and 3. TRAF
degradation occurs in response to signaling by other TNFR superfamily members, and is likely to be a normal
regulatory component of signaling by this receptor family. In this study,
we found that receptor-induced TRAF degradation limits TRAF2-dependent CD40
signals to murine B cells. However, TRAFs 1 and 6 are not degraded in response to CD40
engagement, despite their association with CD40. To better understand the
mechanisms underlying differential TRAF degradation, mixed protein domain
TRAF chimeras were analyzed in murine B cells.
Chimeras containing the TRAF2 zinc (Zn) domains induced effective
degradation, if attached to a TRAF domain that binds to the PXQXT motif of
CD40. However, the Zn domains of TRAF3 and TRAF6 could not induce
degradation in response to CD40, regardless of the TRAF domains to which
they were attached. Our data indicate that TRAF2 serves as the master
regulator of TRAF degradation in response to CD40 signaling, and this
function is dependent upon both the TRAF Zn domains and receptor binding
position.
PMID: 16148124 [PubMed - in process]
Yang M, Hase
H, Legarda-Addison
D, Varughese
L, Seed B, Ting AT.
B cell maturation Ag (BCMA), a member of the TNFR superfamily
expressed on B cells, binds to a proliferation-inducing ligand
(APRIL) and B cell-activating factor of the TNF family (BAFF) but the
specific B cell responses regulated by BCMA remain unclear. This study
demonstrates that ligation of A20 B cells transfected with BCMA induces the expression of CD40,
CD80/B7-1, CD86/B7-2, MHC class II, and CD54/ICAM-1, which subsequently
enhances the presentation of OVA peptide Ag to DO11.10 T cells. BCMA
expression in murine splenic
B cells can be induced with IL-4 and IL-6, allowing subsequent treatment
with APRIL or agonist anti-BCMA to similarly induce Ag presentation. A
comparative analysis of hybrid receptors of TNFR2 fused to the cytoplasmic domains of APRIL/BAFF receptors found that
only BCMA, but not transmembrane activator and
calcium-modulator and cyclophilin ligand interactor or BAFF-R,
is capable of activating Ag presentation. Although all three receptors can
trigger NF-kappaB signaling, only BCMA activates
the JNK pathway conferring on BCMA the specific ability to activate this Ag
presentation response.
PMID: 16116167 [PubMed - in process]
Resveratrol suppresses IL-6-induced
Wung
BS, Hsu MC, Wu CC, Hsieh CW.
Department of Applied Microbiology,
Resveratrol, a polyphenolic
phytoaxelin present in red wine, has been
suggested to protect against atherosclerosis and cardiovascular disease
because of its antioxidant effects. Intercellular adhesion molecule
(ICAM-1), induced by cytokines, has been hypothesized to play a role in the
early events during atherosclerosis. In this study we tested the effects of
resveratrol upon both IL-6-induced ICAM-1 gene
expression and its underlying signaling pathways in endothelial cells (ECs). Resveratrol was found
to inhibit both TNFalpha- and IL-6-induced ICAM-1
gene expression at the promoter, transcriptional and protein levels. Resveratrol also abrogates the tyr705 phosphorylation of STAT3 in IL-6-treated ECs, in a dose- and time-dependent manner. Although quercetin had similar effects, resveratrol
showed higher inhibitory properties following 2-4 h pretreatments. Resveratrol has been shown to induce the activity of
endothelial nitric oxide synthase (eNOS) and increase NO production. Consistent with this,
the treatment of ECs with a NO donor (SNAP)
reduces IL-6-induced STAT3 phosphorylation.
Conversely, exposure of ECs to a NOS inhibitor
reversed the effects of resveratrol upon
IL-6-induced STAT3 phosphorylation. Furthermore, ECs transfected with
constitutively active Rac1 (RacV12) showed increases in ICAM-1 promoter
activity, intracellular reactive oxygen species (ROS) levels and STAT3 phosphorylation, and these increases were attenuated by
resveratrol treatment. In summary, we demonstrate
for the first time that resveratrol inhibits
IL-6-induced ICAM-1 gene expression, in part, by interfering with Rac-mediated pathways via the attenuation of STAT3 phosphorylation. This study therefore provides
important new insights that may contribute to the proposed beneficial
effects of resveratrol in endothelial responses
to cytokines during inflammation.
PMID: 16150460 [PubMed - as supplied by
publisher]