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Molecular and Cellular Biology, July 2000, p. 5330-5342, Vol. 20, No. 14
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

A Pentamer Transcriptional Complex Including tal-1 and Retinoblastoma Protein Downmodulates c-kit Expression in Normal Erythroblasts

Luigi Vitelli,1 Gianluigi Condorelli,2,* Valentina Lulli,1 Trang Hoang,3 Luisella Luchetti,2 Carlo M. Croce,2 and Cesare Peschle1,2,*

Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-55412; Department of Hematology-Oncology, Istituto Superiore di Sanità, 00161 Rome, Italy1; and Clinical Research Institute, Montreal, Canada3

Received 4 October 1999/Returned for modification 30 November 1999/Accepted 19 April 2000

Human proerythroblasts and early erythroblasts, generated in vitro by normal adult progenitors, contain a pentamer protein complex comprising the tal-1 transcription factor heterodimerized with the ubiquitous E2A protein and linked to Lmo2, Ldb1, and retinoblastoma protein (pRb). The pentamer can assemble on a consensus tal-1 binding site. In the pRb- SAOS-2 cell line transiently transfected with a reporter plasmid containing six tal-1 binding site, pRb enhances the transcriptional activity of tal-1-E12-Lmo2 and tal-1-E12-Lmo2-Ldb1 complexes but not that of a tal-1-E12 heterodimer. We explored the functional significance of the pentamer in erythropoiesis, specifically, its transcriptional effect on the c-kit receptor, a tal-1 target gene stimulating early hematopoietic proliferation downmodulated in erythroblasts. In TF1 cells, the pentamer decreased the activity of the reporter plasmid containing the c-kit proximal promoter with two inverted E box-2 type motifs. In SAOS-2 cells the pentamer negatively regulates (i) the activity of the reporter plasmid containing the proximal human c-kit promoter and (ii) endogenous c-kit expression. In both cases pRb significantly potentiates the inhibitory effect of the tal-1-E12-Lmo2-Ldb1 tetramer. These data indicate that this pentameric complex assembled in maturing erythroblasts plays an important regulatory role in c-kit downmodulation; hypothetically, the complex may regulate the expression of other critical erythroid genes.

* Corresponding author. Mailing address: Thomas Jefferson University, Kimmel Cancer Center, Bluemle Life Sciences Bldg., Room 902, 233 South 10th St., Philadelphia, PA 19107-5541. Phone: (215) 503-1763. Fax: (215) 923-1098. E-mail for C. Peschle: Cesare.Peschle{at}mail.tju.edu; E-mail for G. Condorelli: Gianluigi.Condorelli{at}mail.tju.edu.

Molecular and Cellular Biology, July 2000, p. 5330-5342, Vol. 20, No. 14
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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