Volumen: 16 # Number : 2
Publication Date : Mayo - Agosto Year: 2012
Authors: Giuliani R.A.
Abstract: HAMP1 gene can be activated by inflammation or
increase in seric Iron concentration. The marker protein
(HFE) of Hereditary Hemochromatosis type 1 (HH1)
works as an Iron Sensor. Saturated Transferrin (Holo-
Tf) has more affinity for Tf Receptor 1 (TfR1) than by
HFE. Therefore, Holo-Tf removes HFE of its complex
with TfR1 and allows its interaction with TfR2. TfR1/
Holo-Tf is internalized, Fe+3 is released and the complex
recicled to the cell surface. On the contrary, the complex
TfR2/Holo-Tf remains on the cell surface and stimulates
the Erk/MAPK pathway to activate the the Furin gene
(fur). The role of Furin is to convert Pro-Hepcidine into
active Hepcidin and membrane Hemojuvelin (mHJV)
into soluble HJV. Hepcidin induces internalization
and degradation of Ferroportin, which is crtical for the
export of Iron to plasma. Mutations of the HFE, TfR2
or Furin genes are known to cause Iron Overload (HH)
by defect in the function of Furin proconvertase that
transform Preprohepcidin in Prohepcidin. On the other
hand, mHJV works as an “introducer” of BMP6 to its re -
ceptor (BMP-R). The assembling of this ligand-receptor
complex activates the Serine-Threonine Kinase of BMPR,
which phosphorylates rSMADs 1, 3, 5 and promotes
dimerization with SMAD4. The dimers rSMAD/SMAD4
migrates to the nucleus and reacts with SMAD responsive
elements at the HAMP1 promoter. Sach interaction
activates the transcription of Preprohepcidin, which
would be converted in Prohepcidin by Furin. That is
why the deletion of TfR2 also give rise to HH. In addition
to this, Furin converts mHVJ in sHJV by splitting
at AA 332-335 and detachment of its carboxyterminal
domain, which is responsable for its anchoring to the
membrane, through interaction with Glycosylphosphatidylinositol
(GPI). Both versions of HJV, “free” (sHJV)
and bound to GPI (mHJV) have similar affinity for
BMP6 and competes among them for this cytokine. For
that reason the increase in sHJV implies decrease in
the interaction between BMP6/BMP-R. Therefore, Furin
has the dual task to activate Hepcidin and moderate its
transcription by generation of sHJV. Finally the Serinendoprotease
Matriptase-2 (MT-2) degrades mHJV and
helps to moderate the interaction between BMP6-BMP-R.
That is why the deletion of MT-2 enhance the pathway
BMP6-BMP-R/r-SMAD-SMAD4 and expression of Hep -
cidin, increase Ferroportin degradation and provoques
enteral Iron treatment Resistant Iron Deficiency Anemia
(IRIDA). The HAMP1 promoter have also responsive elements
to STAT dimers (inflammation). STAT dimerization
occurs by phosphorylation in Tyrosine (Y) residues,
mediated by Janus Kinases (JAK), and these enzymes are
activated by complexes IL-1/IL1-R or other inflammatory
cytokin-receptor combinations. On the other hand,
Reactive Oxygen Species (ROS) are critical mediators of
the suppression of HAMP1 gene by hypoxia. The ROS
inhibits the interaction among C/EBPα, STAT3 and the
STAT responsive element at the HAMP1 promoter. The
erythropoiesis also modulates the expression of HAMP1
and does it through Growth and Differentiation Factor
15 (GDF15) and Twisted Gastrulation (TWSG1), which
are released by early and late erythroid progenitors
Key words: Hepcidin Hemochromatosis, Bone Morphogenetic
Protein
Pages : 100-105
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