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J. Biol. Chem., Vol. 281, Issue 28, 18918-18926, July 14, 2006

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Transcriptional Activation of the SALL1 by the Human SIX1 Homeodomain during Kidney Development^*

Li Chai¹², Jianchang Yang¹, Chunhui Di, Wei Cui, Kiyoshi Kawakami^¶, Raymond Lai^||, and Yupo Ma³

From the Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, Nevada 89135, The Department of Pathology, Brigham and Women's Hospital Harvard Medical School, Boston, Massachusetts 02115, the ^||Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2B7, Canada and the ^¶Department of Biology, Jichi Medical School, Tochigi 329-0498, Japan

SALL1 is a member of the SAL gene family that encodes a group of putative developmental transcription factors. SALL1 plays a critical role during kidney development as mutations of the human SALL1 gene cause Townes-Brocks syndrome, which is associated with kidney malformation. Deletion of the mouse Sall1 gene results in renal agenesis or severe dysgenesis. To date, little is known about the molecular mechanisms controlling the regulation of SALL1 expression. This report describes the cloning and characterization of the human SALL1 gene promoter. Consensus binding sites were identified for several transcription factors, with multiple sites for WT1 and SIX1. In transient transfection assays, SALL1 promoter activity was higher in HEK-293 human kidney cells and COS-7 monkey kidney cells than in NIH-3T3 fibroblasts, consistent with its role in kidney development. Transcription from the SALL1 promoter was strikingly activated by the SIX1 protein. Utilizing a luciferase reporter gene assay, endogenous or exogenously added SIX1 activated the SALL1 promoter. Overexpression of SIX1 induced a significant increase in the endogenous SIX1 protein. In addition, co-expression of SIX1 and Eya1 resulted in a significant increase in the SALL1 promoter activity when compared with either SIX1 or Eya1 alone. Finally, we demonstrate that SIX1 was able to bind to the SALL1 promoter by retardation assays and that deletion of the putative element of SIX1 significantly diminishes the SALL1 promoter activity response to SIX1 stimulation. Our findings, when taken together, indicate that SALL1 is a likely target gene for SIX1 during kidney development.

Received for publication, January 9, 2006 , and in revised form, April 13, 2006.

^* This work was supported by National Institutes of Health Grants K08 CA097185 and P20 RR016464 (to Y. M.) and K08 DK063220 (to L. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed. E-mail: lchai{at}partners.org. ³To whom correspondence may be addressed: Division of Laboratory Medicine, Nevada Cancer Institute, 10441 W. Twain Ave., Las Vegas, NV 89135. E-mail: yma{at}nvcancer.org.

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