| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Pediatrics, Section of Pediatric Nephrology, Tulane University Health Sciences Center, New Orleans, LA, USA
* To whom correspondence should be addressed. E-mail: seldahr{at}tulane.edu.
Despite a wealth of knowledge regarding the early steps of epithelial differentiation, little is known about the mechanisms responsible for terminal nephron differentiation. The bradykinin B2 receptor (B2R) regulates renal function and integrity and its expression is induced during terminal nephron differentiation. This study investigates the transcriptional regulation of the B2R during kidney development. The rat B2R 5'- flanking region has a highly conserved cis-acting enhancer in the proximal promoter consisting of contiguous binding sites for the transcription factors Cyclic AMP Response Element Binding Protein (CREB), p53, and Kruppel-like Factor (KLF-4). The B2R enhancer drives reporter gene expression in IMCD-3 cells but is considerably weaker in other cell types. Site-directed mutagenesis and expression of dominant negative mutants demonstrated the requirement of CREB DNA binding and Ser-133 phosphorylation for optimal enhancer function. Moreover, helical phasing experiments showed that disruption of the spatial organization of the enhancer inhibits B2R promoter activity. Several lines of evidence indicate that cooperative interactions among the three transcription factors occur in vivo during terminal nephron differentiation: a) CREB, p53 and KLF-4 are co-expressed in B2R-positive differentiating cells, b) The maturational expression of B2R correlates with CREB/p53/KLF-4 DNA-binding activity, c) Assembly of CREB, p53 and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation, and d) CREB and p53 occupancy of the B2R enhancer is cooperative. These results demonstrate that combinatorial interactions among the transcription factors, CREB, p53 and KLF-4, and the co-activator CBP, may be critical for the regulation of B2R gene expression during terminal nephron differentiation.
This article has been cited by other articles:
|
|
 |
|
  A. Pozzi and R. Zent Integrins, Extracellular Matrix, and Terminal Differentiation of Renal Epithelial Cells J. Am. Soc. Nephrol., June 1, 2008; 19(6): 1043 - 1044. [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. El-Dahr, K. Aboudehen, and Z. Saifudeen Transcriptional control of terminal nephron differentiation Am J Physiol Renal Physiol, June 1, 2008; 294(6): F1273 - F1278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Shen, L. M. Harrison-Bernard, A. J. Fuller, V. Vanderpool, Z. Saifudeen, and S. S. El-Dahr The Bradykinin B2 Receptor Gene Is a Target of Angiotensin II Type 1 Receptor Signaling J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1140 - 1149. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Fan, J. Stefkova, and S. S. El-Dahr Susceptibility to metanephric apoptosis in bradykinin B2 receptor null mice via the p53-Bax pathway Am J Physiol Renal Physiol, September 1, 2006; 291(3): F670 - F682. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Zamorano, S. Suchindran, and J. V. Gainer 3'-Untranslated region of the type 2 bradykinin receptor is a potent regulator of gene expression Am J Physiol Renal Physiol, February 1, 2006; 290(2): F456 - F464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Bates Transcriptional control of renal collecting duct development Am J Physiol Renal Physiol, May 1, 2005; 288(5): F897 - F898. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
