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Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3945-3950
Differential expression of a novel C-terminally
truncated splice form of SMAD5 in hematopoietic stem cells
and leukemia
Yunfang Jiang,
Hong Liang,
Wei Guo,
Lazar
V. Kottickal, and
Lalitha Nagarajan
From the Department of Molecular Genetics, MD Anderson Cancer
Center, University of Texas, Houston, TX.
SMADs are evolutionarily conserved transducers of the
differentiation and growth arrest signals from the transforming growth factor/BMP (TGF/BMP) family of ligands. Upon receptor activation, the
ligand-restricted SMADs1-35 are phosphorylated in the
C-terminal MH2 domain and recruit the common subunit SMAD4/DPC-4 gene
to the nucleus to mediate target gene expression. Frequent inactivating
mutations of SMAD4, or less common somatic mutations of
SMAD2 seen in solid tumors, suggest that these genes have a
suppressor function. However, there have been no identified mutations
of SMAD5, although the gene localizes to the critical region of loss in
chromosome 5q31.1 (chromosome 5, long arm, region 3, band
1, subband 1) in myelodysplasia (MDS) and acute myelogenous leukemia
(AML). A ubiquitously expressed novel isoform,
SMAD5 , encodes a 351 amino acid protein with a truncated MH2 domain and a unique C-terminal tail of 18 amino acids, which may be the functional equivalent of inactivating mutations. The levels of SMAD5 transcripts are
higher in the undifferentiated CD34+ hematopoietic stem
cells than in the terminally differentiated peripheral blood
leukocytes, thereby implicating the form in stem cell homeostasis.
Yeast 2-hybrid interaction assays reveal the lack of physical
interactions between SMAD5 and SMAD5 or SMAD4. The expression of
SMAD5 may represent a novel mechanism to
protect pluripotent stem cells and malignant cells from the growth
inhibitory and differentiation signals of BMPs.
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