Phosphorylation of AML1/RUNX1 regulates its degradation and nuclear matrix association

Joseph R. Biggs, Youhong Zhang, Luke F. Peterson, Marileila Garcia, Dong Er Zhang, Andrew Kraft

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The acute myeloid leukemia 1 (AML1) transcription factors are key regulators of hematopoietic differentiation. Cellular AML1c protein is found in the nucleus and can be separated into two fractions, one soluble in buffers containing salt and nonionic detergent and the other insoluble and tightly bound to the nuclear matrix. We find that the AML1c protein is modified by both phosphorylation and ubiquitination. Our studies show that the majority of the ubiquitinated AML1c is associated with the insoluble nuclear matrix. Treatment of cells with the proteasome inhibitor PS341 (Velcade, Bortezomib) increases the levels of ubiquitinated AML1c. Mutation of the four phosphorylation sites necessary for transcriptional regulation (serine 276, serine 293, serine 303, and threonine 300) mimics the effects of the proteasome inhibitor, increasing the levels of ubiquitinated, matrix-bound AML1c. We find that the soluble and insoluble forms of AML1c are degraded at a similar rate. However, mutation of these four serine/threonine residues statistically increases the half-life of the matrix-associated AML1c. Thus, phosphorylation of AML1c on specific serine/threonine residues controls both transcriptional activity and rate of degradation.

Original languageEnglish (US)
Pages (from-to)391-401
Number of pages11
JournalMolecular Cancer Research
Volume3
Issue number7
DOIs
StatePublished - Jul 2005
Externally publishedYes

Fingerprint

Nuclear Matrix
Acute Myeloid Leukemia
Serine
Phosphorylation
Threonine
Proteasome Inhibitors
Mutation
Ubiquitination
Detergents
Half-Life
Buffers
Proteins
Transcription Factors
Salts

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Phosphorylation of AML1/RUNX1 regulates its degradation and nuclear matrix association. / Biggs, Joseph R.; Zhang, Youhong; Peterson, Luke F.; Garcia, Marileila; Zhang, Dong Er; Kraft, Andrew.

In: Molecular Cancer Research, Vol. 3, No. 7, 07.2005, p. 391-401.

Research output: Contribution to journalArticle

Biggs, Joseph R. ; Zhang, Youhong ; Peterson, Luke F. ; Garcia, Marileila ; Zhang, Dong Er ; Kraft, Andrew. / Phosphorylation of AML1/RUNX1 regulates its degradation and nuclear matrix association. In: Molecular Cancer Research. 2005 ; Vol. 3, No. 7. pp. 391-401.
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