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The Smad5 Gene Is Involved in the Intracellular Signaling
Pathways That Mediate the Inhibitory Effects of Transforming
Growth Factor- on Human Hematopoiesis
Edward Bruno,
Stephen K. Horrigan,
David Van Den Berg,
Elen Rozler,
Priscilla R. Fitting,
Steven T. Moss,
Carol Westbrook, and
Ronald Hoffman
From the Hematology/Oncology Section, Department of Medicine of the
University of Illinois at Chicago, Chicago, IL.
Signals from transforming growth factor- (TGF-), a
bifunctional regulator of the proliferation of hematopoietic progenitor cells, have been recently shown to be transduced by five novel human
genes related to a Drosophila gene termed MAD (mothers against the
decapentaplegic gene). We showed by reverse transcriptase polymerase
chain reaction that the RNA from one homologue gene, Smad5, was present
in the immortalized myeloid leukemia cell lines, KG1 and HL60, in bone
marrow mononuclear and polymorphonuclear cells, as well as in purified
CD34+ bone marrow cells. Therefore, we studied the role
of this gene in the regulation of human hematopoiesis by TGF-.
TGF-1 and TGF-2 significantly inhibited myeloid, erythroid,
megakaryocyte, and multilineage colony formation as assayed in
semisolid culture systems. The levels of Smad5 mRNA in
CD34+ cells were decreased by antisense but not sense
oligonucleotides to Smad5. Preincubation of CD34+ marrow
cells with two sense oligonucleotides to Smad5 did not reverse the
inhibitory effects of TGF- on hematopoietic colony formation.
However, preincubation with two antisense oligonucleotides to Smad5
reversed the inhibitory effects of TGF-. These data show that the
Smad5 gene is involved in the signaling pathway by which TGF-
inhibits primitive human hematopoietic progenitor cell proliferation
and that Smad5 antisense oligonucleotides can interrupt this signal.
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 1917-1923
© 1998 by The American Society of Hematology.
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