AML1 stimulates G1 to S progression via its transactivation domain View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2002-05

AUTHORS

Florence Bernardin, Alan D Friedman

ABSTRACT

Inhibition of AML1-mediated transactivation potently slows G1 to S cell cycle progression. In Ba/F3 cells, activation of exogenous AML1 (RUNX1)-ER with 4-hydroxytamoxifen prevents inhibition of G1 progression mediated by CBFbeta-SMMHC, a CBF oncoprotein. We expressed three AML1-ER variants with CBFbeta-SMMHC in Ba/F3 cells. In these lines, CBFbeta-SMMHC expression is regulated by the zinc-responsive metallothionein promoter. Deletion of 72 AML1 C-terminal residues, which includes a transrepression domain, did not alter the activity of AML1-ER, whereas further deletion of 98 residues, removing the most potent AML1 transactivation domain (TAD), prevented rescue of cell cycle inhibition. Notably, the two variants which did not stimulate G1 exacerbated CBFbeta-SMMHC-mediated cell cycle arrest, suggesting that they dominantly inhibit AML1 activities. In addition, the two variants which stimulated G1 also induced apoptosis in 5-15% of the cells, an effect consistent with excessive G1 stimulation. These observations indicate that AML1 activates transcription of one or more genes critical for the G1 to S transition via its C-terminal transactivation domain. Inactivation of AML in acute leukemia is expected to slow proliferation unless additional genetic alterations co-exist which accelerate G1. More... »

PAGES

1205447

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.onc.1205447

DOI

http://dx.doi.org/10.1038/sj.onc.1205447

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1010570511

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/12082641


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61 schema:description Inhibition of AML1-mediated transactivation potently slows G1 to S cell cycle progression. In Ba/F3 cells, activation of exogenous AML1 (RUNX1)-ER with 4-hydroxytamoxifen prevents inhibition of G1 progression mediated by CBFbeta-SMMHC, a CBF oncoprotein. We expressed three AML1-ER variants with CBFbeta-SMMHC in Ba/F3 cells. In these lines, CBFbeta-SMMHC expression is regulated by the zinc-responsive metallothionein promoter. Deletion of 72 AML1 C-terminal residues, which includes a transrepression domain, did not alter the activity of AML1-ER, whereas further deletion of 98 residues, removing the most potent AML1 transactivation domain (TAD), prevented rescue of cell cycle inhibition. Notably, the two variants which did not stimulate G1 exacerbated CBFbeta-SMMHC-mediated cell cycle arrest, suggesting that they dominantly inhibit AML1 activities. In addition, the two variants which stimulated G1 also induced apoptosis in 5-15% of the cells, an effect consistent with excessive G1 stimulation. These observations indicate that AML1 activates transcription of one or more genes critical for the G1 to S transition via its C-terminal transactivation domain. Inactivation of AML in acute leukemia is expected to slow proliferation unless additional genetic alterations co-exist which accelerate G1.
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