The Extracellular Signal-Regulated Kinase Pathway Phosphorylates AML1, an Acute Myeloid Leukemia Gene Product, and Potentially Regulates Its Transactivation Ability

Tanaka, Tomoyuki; Kurokawa, Mineo; Ueki, Kohjiro; Tanaka, Kozo; Imai, Yoichi; Mitani, Kinuko; Okazaki, Kenji; Sagata, Noriyuki; Yazaki, Yoshio; Shibata, Yoichi; Kadowaki, Takashi; Hirai, Hisamaru

doi:10.1128/mcb.16.7.3967

Cited by 152Acute Myeloid Leukemia ResearchProtein Tyrosine PhosphatasesRetinoids in leukemia and cellular processes

The Extracellular Signal-Regulated Kinase Pathway Phosphorylates AML1, an Acute Myeloid Leukemia Gene Product, and Potentially Regulates Its Transactivation Ability

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Tanaka, Tomoyuki, Kurokawa, Mineo, Ueki, Kohjiro, Tanaka, Kozo, Imai, Yoichi, Mitani, Kinuko, Okazaki, Kenji, Sagata, Noriyuki +4 more·1996·Molecular and Cellular Biology

DOI 10.1128/mcb.16.7.3967PMC PMC231393

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Abstract

AML1 (also called PEBP2alphaB, CBFA2, or CBFalpha2) is one of the most frequently disrupted genes in chromosome abnormalities seen in human leukemias. It has been reported that AML1 plays several pivotal roles in myeloid hematopoietic differentiation and other biological phenomena, probably through the transcriptional regulation of various relevant genes. Here, we investigated the mechanism of regulation of AML1 functions through signal transduction pathways. The results showed that AML1 is phosphorylated in vivo on two serine residues within the proline-, serine-, and threonine-rich region, with dependence on the activation of extracellular signal-regulated kinase (ERK) and with interleukin-3 stimulation in a hematopoietic cell line. These in vivo phosphorylation sites of AML1 were phosphorylated directly in vitro by ERK. Although differences between wild-type AML1 and phosphorylation site mutants in DNA-binding affinity were not observed, we have shown that ERK-dependent phosphorylation potentiates the transactivation ability of AML1. Furthermore the phosphorylation site mutations reduced the transforming capacity of AML1 in fibroblast cells. These data indicate that AML1 functions are potentially regulated by ERK, which is activated by cytokine and growth factor stimuli. This study provides some important clues for clarifying unidentified facets of the regulatory mechanism of AML1 function.

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ERK-mediated phosphorylation of AML1A at serines 249 and 266 (AML1B serines 276 and 293) can raise the activity of an AML1-responsive reporter.
“The activation of an AML1-responsive reporter by AML1A can be increased following phosphorylation by ERK on serines 249 and 266 (corresponding to serines 276 and 293 of AML1B) (68).”
From Multiple Functional Domains of AML1: PU.1 and C/EBPα Synergize with Different Regions of AML1 (1998) · cites this paper as [68]
The Results (Fig. 2) identify the protein carrying the ERK-dependent sites as AML1b and state that AML1a lacks the PST region; no ERK-dependent phosphorylation shift was detected for AML1a. The Results (Fig. 3) assign the sites to AML1b serines 249 and 266 and say that its serine 276 was not a detectable ERK-dependent phosphorylation site. The reporter increase described in the Results (Fig. 8) therefore supports the effect for AML1b, not the isoform and residue mapping in the claim. (LLM, conf=0.91)
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Authors: Tanaka, T., Kurokawa, M., Ueki, K., Tanaka, K., Imai, Y., Mitani, K., Okazaki, K., Sagata, N., Yazaki, Y., Shibata, Y., Kadowaki, T., & Hirai, H.
Affiliations: The University of Tokyo (JP)
Kurume University (JP)
Corresponding author: Hirai, Hisamaru
ORCID: Tanaka, Tomoyuki
Kurokawa, Mineo
Ueki, Kohjiro
Tanaka, Kozo
Imai, Yoichi
Mitani, Kinuko
Kadowaki, Takashi
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 1996-07-01
Volume: 16
Issue: 7
Pages: 3967-3979
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.16.7.3967
PMC: PMC231393
OpenAlex: W2136727607
Cited by: 152
References: 101
Citations by year: 2026: 1 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 6 · 2016: 2 · 2015: 5 · 2014: 6 · 2013: 3 · 2012: 9
FWCI: 3.46
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Howard Hughes Medical Institute
National Cancer Research Institute
National Cancer Institute
Topics: Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
Keywords: RUNX1, extracellular signal-regulated kinase, ERK1/2 phosphorylation, serine phosphorylation, transcriptional activation, interleukin-3, hematopoietic differentiation, transcriptional regulation, leukemia, phosphorylation site mutants
MeSH terms: Acute Disease, Amino Acid Sequence, Animals, Cell Line, Chlorocebus aethiops, Chromosome Aberrations, DNA-Binding Proteins, Humans, Leukemia, Myeloid, Luciferases, Molecular Sequence Data, Neoplasm Proteins, Phosphorylation, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Transcription Factors, Transfection, Signal Transduction, Transcriptional Activation, Calcium-Calmodulin-Dependent Protein Kinases, Chromosome Disorders, Core Binding Factor Alpha 2 Subunit

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The Extracellular Signal-Regulated Kinase Pathway Phosphorylates AML1, an Acute Myeloid Leukemia Gene Product, and Potentially Regulates Its Transactivation Ability

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