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Blood, 1 March 2001, Vol. 97, No. 5, pp. 1266-1273
HEMATOPOIESIS
Initiation of polyoma virus origin-dependent DNA replication
through STAT5 activation by human granulocyte-macrophage
colony-stimulating factor
Sumiko Watanabe,
Rong Zeng,
Yutaka Aoki,
Tohru Itoh, and
Ken-ichi Arai
From the Department of Molecular and Developmental
Biology, Institute of Medical Science, Core Research for Evolutional
Science and Technology, Tokyo, Japan.
Several lines of evidence indicate that transcriptional activation
is coupled with DNA replication initiation, but the nature of
initiation of DNA replication in mammalian cells is unclear. Polyoma
virus replicon is an excellent system to analyze the initiation of DNA
replication in murine cells because its replication requires an
enhancer, and all components of replication machinery, except for DNA
helicase large T antigen, are supplied by host cells. This system was
used to examine the role of signal transducer and activator of
transcription (STAT5) in replication initiation of polyoma replicon in
the mouse lymphoid cell line BA/F3. The plasmid with tandem repeats of
consensus STAT5 binding sites followed by polyoma replication origin
was replicated by stimulation with human granulocyte-macrophage
colony-stimulating factor (hGM-CSF) in the presence of polyoma large T
antigen in BA/F3 cells. Mutation analysis of the hGM-CSF receptor  subunit revealed that only the box1 region is essential, and the
C-terminal tyrosine residues are dispensable for the activity. Addition
of the tyrosine kinase inhibitor genistein suppressed this replication
without affecting transcriptional activation of STAT5. Because deletion
analysis of STAT5 indicates the importance of the C-terminal
transcriptional activation domain of STAT5 for the initiation of
replication, the role of this region in the activation of replication
was examined with a GAL4-STAT5 fusion protein. GAL4-STAT5 activated
replication of the plasmid containing tandem repeats of GAL4 binding
sites and polyoma replication origin in BA/F3 cells. Mutation analysis of GAL4-STAT5 indicated that multiple serine residues coordinately have a role in activating replication. This is the first direct evidence indicating the potential involvement of STAT5 in replication.
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