Transcriptional induction of the urokinase receptor gene by a constitutively active Src: Requirement of an upstream motif (-152/-135) bound with Sp1

Heike Allgayer, Heng Wang, Gary E. Gallick, Andrea Crabtree, Andrew Mazar, Terence Jones, Alan J. Kraker, Douglas D. Boyd*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Since c-src overexpression increases colonic cell invasiveness and because both Src activity and urokinase receptor protein are elevated in invasive colon cancers, the present study was undertaken: 1) to determine if a constitutively active Src regulates urokinase receptor expression and 2) to identify required cis-elements and trans-acting factors. SW480 colon cancer cells transfected with an expression plasmid (c-srcY527F) encoding a constitutively active Src protein manifested increased urokinase receptor gene expression and Src activity. Treatment of the src transfectants with a Src-inhibitor (PD173955) reduced urokinase receptor protein levels and laminin degradation. Inasmuch as we recently implicated an upstream region of the urokinase receptor promoter (-152/-135) in constitutive urokinase receptor expression, we determined its role for the induction by src. Whereas the activity of a CAT reporter driven by this region was stimulated by c- srcY527F, the u-PAR promoter mutated at the Sp1-binding motif in the -152/- 135 region was not. Nuclear extracts from the src transfectants demonstrated increased Sp1 binding to region -152/-135 compared with those from SW480 cells. Finally, endogenous urokinase receptor protein amounts in 10 colon cancers and corresponding normal colon correlated with Src specific activity. These data suggest that urokinase receptor gene expression is regulated by Src partly via increased Sp1 binding.

Original languageEnglish (US)
Pages (from-to)18428-18437
Number of pages10
JournalJournal of Biological Chemistry
Volume274
Issue number26
DOIs
StatePublished - Jun 25 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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