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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3325-3332
NEOPLASIA
Binding of Sp1 to the proximal promoter links constitutive
expression of the human uPA gene and invasive potential of PC3
cells
Inés Ibañez-Tallon,
Carmelo Ferrai,
Elena Longobardi,
Ileana Facetti,
Francesco Blasi, and
Massimo P. Crippa
From the Laboratory of Molecular Genetics, Department
of Biological and Technological Research (DIBIT) and
Università Vita-Salute, S. Raffaele Scientific Institute, Milano,
Italy.
Activated transcription of the urokinase-type plasminogen activator
(uPA) gene depends on the enhancer, located approximately 2 kb from the
start of transcription. The proximal promoter, driving basal
transcription, contains a GC-/GA-rich sequence immediately upstream of the TATA box. We have investigated the role played by this element in the transcription of the uPA gene in HeLa and PC3
cells, which do not express or constitutively express the gene,
respectively. This region binds either Sp1 or Sp3, as monomers or
multimers, but not a combination of the 2 proteins. The more efficient
binding of Sp1 to the proximal promoter in PC3 cells is correlated to
its phosphorylation state. Polymerase chain reaction (PCR)-coupled, chromatin immunoprecipitation experiments with anti-Sp1
antibodies indeed show an enrichment of proximal promoter sequences in
PC3 cells and support the observed difference in transcription levels
from proximal promoter constructs in HeLa versus PC3 cells.
Furthermore, overexpression of Sp1 increases transcription from the
reporter construct in HeLa cells, whereas in PC3 cells, overexpression
of Sp3 does not reduce transcription from the same construct,
indicating that the Sp1/Sp3 balance cannot be shifted. We conclude that
the GC-/GA-rich element of the uPA regulatory region is an
independent functional element, regulated by Sp family proteins.
Phosphorylation of Sp1 determines the presence in vivo and the
functionality of this element in PC3 cells. Thus, the cellular context
determines the relevance of the GC-/GA-rich region in uPA gene
transcription, which contributes to constitutive gene expression,
related, in turn, to the invasive phenotype.
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