Highlights:- An overexpression
of TRAF6 gene in the hematopoietic stem cells lead to poor production of
blood cells finds a study from the Cincinnati Children's Hospital.
- A new substrate
of TRAF6 called hnRNPA1 is also an RNA binding protein.
- TRAF6 and its
substrate could function as a potential target for drug therapy.
A
new mechanism that controls blood cell function and possible biomarkers for
treating myelodysplasia syndrome (MDS) have been identified by a research team
from Cincinnati Children's hospital.
The
research study was published in the Journal
Nature
Immunology.
‘TRAF6 is a potential new target for Drug Therapy to treat pre-malignant bone marrow disorders’
Myelodysplasia
syndrome is a group of pre-malignant conditions that arise because of the
insufficient healthy blood cells that are produced due to poor bone marrow
function. This condition can lead to the development of
acute myeloid leukemia (AML).
AML
is an invasive and a fast-spreading blood cancer, which can be fatal if treatment is not initiated quickly.
Dr.
Daniel Starczynowski, a cancer biologist, and his research team found that
overexpression identified may increase production of a protein, TRAF6, in blood
cells resulting in the development of myelodysplasia syndromes. This protein is
known to function as a detector of pathogen entry and is vital in immune
reactions.
Cincinnati
Children's Hospital Medical Center's Dr. Starczynowski who is a member of the
Division of Experimental Hematology and Cancer Biology said that his research
team found that an overexpression of the protein TRAF6 in the hematopoietic
stem cells of mice leads to poor development of blood cells and a
failure of the bone marrow to function well.
The study conducted by the
research team could be used for a number of therapeutic purposes with TRAF 6 as
the target for drug therapy.
RNA Binding Protein
The
studies were conducted on mouse models as well as on human models. While
testing in mouse and human MDS and AML samples,
the research team identified
a new substrate of TRAF6 called hnRNPA1. This substrate is an
RNA
binding protein and was also found to be associated with Cdc42, which is a
protein that aids in the regulation of blood cells and has also been identified
in the development of certain forms of cancer.
The
proteins and their substrates that were identified in this study can also be
used as a target for drug therapy. These
are caused by the overexpression of TRAF6. Dr. Starczynowski further stated
that the use of these proteins as therapeutic targets will be studied in mouse
models.
The
advancements in molecular analysis, spearheaded by global proteomic analysis of
disease cells allow identification of the entire protein system that leads to
the development of a diseased state. In this study, new molecular biomarkers
and targets for therapy were identified after global proteomic analysis of
leukemia cells, which provided identification of the entire range of proteins
that were regulated by TRAF6 in leukemia
cells.
RNA Isoform Expression
The
potential for the use of TRAF6 as a target for drug therapy was established in
this study but it also revealed another critical aspect, the protein was also
found to manage the expression of RNA isoform In response to various pathogens.
This is a vital step in the translation process which involves the conversion
of the genetic code into protein. Dr. Starczynkowski said that in the present
study the RNA isoform expression that was regulated by TRAF6 is important in
the development and function of blood cells and showcases another aspect of
cellular behavior in response to infection.
TRAF6 and cancer
Progression
A previous study by Heng Sun et al titled
"TRAF6 upregulates expression of HIF-1 and promotes tumor angiogenesis" showed
that TNFR-associated factor TRAF6 played an important role in the activation of
NF-κB, that was involved in the regulation of innate immune responses along
with adaptive immune responses. TRAF6 interactions were important in the
determination of receptor-associated cell death. TRAF6 has been implicated in
cancer but its contributions have not been investigated deeply.
It
was found that TRAF6 increases expression of a factor called the
hypoxia-inducible factor 1 (HIF-1). Though TRAF6 alters the levels of HIF-1
protein it has very little influence on the mRNA level. The results of the
study show that TRAF6 increases HIF-1 expression and promotes tumor
angiogenesis.
TRAF6
has been implicated in cancer disease progression. However, this is the first
study that details the effect of the protein in the development of
hematopoietic cells and also in the process of gene expression. The therapeutic
targets that were identified can be used for drug therapy against Acute Myeloid
Leukemia as well as for myelodysplasia syndrome, providing better care.
References:- TRAF6 upregulates expression of HIF-1 and promotes tumor angiogenesis - (http://cancerres.aacrjournals.org/content/canres/early/2013/05/30/0008-5472.CAN-13-0370.full.pdf)
Source-Medindia
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