Upstream and Downstream of the Human Leukemia Associated Transcription Factor RUNX1/AML1

Yoram Groner
Dept. of Molecular Genetics
The Weizmann Institute of Science,
Rehovot, ISRAEL
telephone: 972-8-9343972
fax: 972-8-9344108
prestype: Platform

Amir Pozner, Talia Polak, Thorsten Bangsow, Yael Bernstein, Varda Negreanu, Dalia Goldenberg, Tali Ben Aziz-Aloya, Carmen Anghel-Bangsow, Nir Rubins, Joan D. Bettoun, Ditsa Levanon, and Yoram Groner
Dept. of Molecular Genetics, The Weizmann Inst. of Science, Rehovot, ISRAEL

The RUNX1 gene on human chromosome 21q22.1 belongs to the "runt domain" gene family of transcription factors (also known as AML/CBFA/PEBP2). In human three highly conserved runt domain genes have been identified: RUNX1 on chromosome 21q22.1, RUNX2 on chromosome 6p21 and RUNX3 on chromosome 1p36.1. RUNX1 is a key regulator of hematopoiesis and a frequent target of leukemia associated chromosomal translocations. RUNX2 on the other hand functions as a key regulator of osteogenesis. The three RUNX gene-products bind to the same DNA sequence; therefore, their pleotropic functions must result from a regulated, temporally specific and tissue-specific expression as well as interactions with other transcriptional regulators.

Complete DNA sequence of RUNX1 was recently obtained within the framework of chromosome 21 mapping and sequencing consortium and the structural/functional features of the gene were established in our lab.

We found that two distinct promoter regions, designated distal (D) and proximal (P), control the transcription of RUNX1. These promoter regions are separated by a particularly large intron of 160 Kb. RUNX1 D and P promoters mediate transcription of mRNAs with discrete 5' UTRs, the D-UTR (0.45 Kb) and P-UTR (1.6 Kb). These 5’UTRs function as translational regulators thereby creating an additional level of control. RUNX1 mRNAs bearing D-UTR are readily translated via cap-dependent mechanism; wherease translation of mRNAs with the uncommonly long P-UTR is mediated through usage of the internal ribosome entry site (IRES) of this UTR. The temporal and spatial expression of RUNX1 promoters during mouse embryogenesis is studied using promoter-lac-z constructs in transgenic mice. RUNX1 expression also involves complex patterns of alternative splicing generating a diverse collection of mRNAs with coding regions varying in size between 188-480 aa. The short proteins usually lack the so-called transactivation domain (TAD). We showed that one of the short isoform RUNX1/p26, but not the full length RUNX1/p49, suppressed in vivo tumor growth and differentiation of ES cells derived teratocarcinomas. Most TAD containing RUNX proteins terminate with an identical C-terminal VWRPY motif which serves to recruit the co- repressor Groucho/TLE. We demonstrated direct interaction between Gro/TLE and RUNX1/p49 and show that this interaction lead to transcriptional repression of RUNX1 regulated target genes. The protein isoform RUNX1/p51, which is almost identical to RUNX1/p49 but lacks VWRPY, did not interact with Gro/TLE. These data highlight the biological significance of the alternatively spliced RUNX1 isoforms.

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