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Originally published In Press as doi:10.1074/jbc.M201407200 on April 9, 2002

J. Biol. Chem., Vol. 277, Issue 29, 25877-25883, July 19, 2002
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The Rod cGMP-phosphodiesterase beta -Subunit Promoter Is a Specific Target for Sp4 and Is Not Activated by Other Sp Proteins or CRX*

Leonid E. LernerDagger §, Yekaterina E. GribanovaDagger , Leigh Whitaker||, Barry E. Knox||**, and Debora B. FarberDagger §Dagger Dagger

From the Dagger  Jules Stein Eye Institute, Department of Ophthalmology, UCLA School of Medicine, § Molecular Biology Institute, Los Angeles, California 90095, and the || Department of Biochemistry and Molecular Biology and ** Department of Ophthalmology, State University of New York Upstate Medical University, Syracuse, New York 13210

The beta -subunit of cGMP-phosphodiesterase (beta -PDE) is a key protein in phototransduction expressed exclusively in rod photoreceptors. It is necessary for visual function and for structural integrity of the retina. beta -PDE promoter deletions showed that the -45/-23 region containing a consensus Crx-response element (CRE) was necessary for low level transcriptional activity. Overexpressed Crx modestly transactivated this promoter in 293 human embryonic kidney cells; however, mutation of CRE had no significant effect on transcription either in transfected Y79 retinoblastoma cells or Xenopus embryonic heads. Thus, Crx is unlikely to be a critical beta -PDE transcriptional regulator in vivo. Interestingly, although the beta /GC element (-59/-49) binds multiple Sp transcription factors in vitro, only Sp4, but not Sp1 or Sp3, significantly enhanced beta -PDE promoter activity. Thus, the Sp4-mediated differential activation of the beta -PDE transcription defines the first specific Sp4 target gene reported to date and implies the importance of Sp4 for retinal function. Further extensive mutagenesis of the beta -PDE upstream sequences showed no additional regulatory elements. Although this promoter lacks a canonical TATA box or Inr element, it has the (T/A)-rich beta /TA sequence located within the -45/-23 region. We found that it binds purified TBP and TFIIB in gel mobility shift assays with cooperative enhancement of binding affinity.

* This work was supported in part by NEI Grants KO8 EY00367 (to L. E. L.), EY02651 (to D. B. F.), EY11256, and EY12975 (to B. E. K.) from the National Institutes of Health, The Foundation Fighting Blindness (to D. B. F.), and a challenge grant from Research to Prevent Blindness (to B. E. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Performed this work as part of a Ph.D. thesis research.

Dagger Dagger Recipient of a Research to Prevent Blindness Senior Scientist Investigators award. To whom correspondence should be addressed: Jules Stein Eye Institute, Dept. of Ophthalmology, UCLA School of Medicine, 100 Stein Plaza, Los Angeles, CA 90095. Tel.: 310-206-7375; Fax: 310-794-2144; E-mail: farber@jsei.ucla.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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