c-Myb acetylation at the carboxyl-terminal conserved domain by transcriptional co-activator p300

Tomita, Akihiro; Towatari, Masayuki; Tsuzuki, Shinobu; Hayakawa, Fumihiko; Kosugi, Hiroshi; Tamai, Katsuyuki; Miyazaki, Toshiaki; Kinoshita, Tomohiro; Saito, Hidehiko

doi:10.1038/sj.onc.1203329

Cited by 118 publications

(90 citation statements)

References 42 publications

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“…The KIX domain interacts directly with the c-Myb transactivation domain, whilst the C/H2 region binds the c-Myb negative regulatory domain (NRD; within which lies the CR). CBP has been found to acetylate the c-Myb NRD at ®ve lysines (Tomita et al, 2000;Sano and Ishii, 2001). As all of these residues are conserved in A-Myb and four are conserved in the BMyb CR, it may be suggested that the mechanism of CBP co-activation is similar between the members of the Myb family.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cyclin A/Cdk2 phosphorylation impairs B-Myb transactivation function without affecting interactions with DNA or the CBP coactivator

2001

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Expression of the B-Myb transcription factor is directed by an E2F-dependent transcriptional mechanism to late G1 and S phases of the cell cycle, where its transactivation properties are enhanced post-translationally by cyclin A/Cdk2-mediated phosphorylation. Other experiments have shown that removal of the B-Myb Cterminus constitutively activates both transactivation and DNA-binding activities, suggesting that autoregulation by this inhibitory domain is counteracted by phosphorylation. We report here on further experiments to examine this hypothesis. The importance of this modi®cation was ®rst emphasized by showing that cotransfected dominant-negative Cdk2 (Cdk2DN) substantially reduced B-Myb transactivation activity. We then attempted to map the autoregulatory domain by analysing a series of progressively deleted C-terminal B-Myb mutants. Removal of just 29 C-terminal aa increased transactivation appreciably, however, maximal activity required removal of 143 amino acids (as in BMyb+561). Enhanced B-Myb+561 function correlated with the acquisition of DNA binding activity to a single Myb binding site (MBS) oligonucleotide as determined by bandshift assays, however, further assays showed that even wt B-Myb could bind a DNA fragment containing three MBS. Although transactivation by B-Myb was severely dependent on hyperphosphorylation, neither inhibiting this activity by co-transfecting Cdk2DN nor augmenting it with cyclin A resulted in signi®cant e ects on DNA-binding. We also found that B-Myb could synergize with the CBP coactivator and that this cooperativity was cyclin A/Cdk2-dependent. Despite this, the physical association between these proteins was not in¯uenced by the B-Myb phosphorylation status. We discuss these ®ndings in relation to the autoregulation of B-Myb by the C-terminal domain. Oncogene (2001) 20, 3376 ± 3386.

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Section: Discussionmentioning

confidence: 99%

Inhibition of cyclin A/Cdk2 phosphorylation impairs B-Myb transactivation function without affecting interactions with DNA or the CBP coactivator

2001

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“…Further, inhibition of C-Myb activity also causes reduced cell survival and proliferation (24). Function of C-Myb protein is also acetylation dependent (25). p300 acetylates the conserved C-terminal domain of C-Myb which stimulates its DNA binding activity.…”

Section: Classification Of Nonhistone Substrates Of Hats and Hdacsmentioning

confidence: 99%

Transcriptional Regulation by the Acetylation of Nonhistone Proteins in Humans – A New Target for Therapeutics

Das

Kundu

2005

IUBMB Life (International Union of Biochemistry and Molecular B

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SummaryGene expression from the dynamic chromatin template is regulated by certain key cellular players that cause post-translational modifications of both histones and nonhistone proteins. The acetyltransferases and deacetylases are two such key groups of enzymes that play crucial roles in maintaining the reversible acetylation status of histones and nonhistone proteins. Emerging evidence suggests that acetylation of nonhistone protein is equally important in the transcription regulation as the histone acetylation. Since dysfunction of HATs and HDACs leads to several diseases, aberrant acetylation of nonhistone protein is also associated with diseases. Small molecule modulators of these enzymes, which may help in maintaining the normal cellular acetylation status of these proteins, have important therapeutic implications. IUBMB Life, 57: 137 -148, 2005

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“…c-Myb is also regulated by post-transcriptional modifications including sumoylation, phosphorylation, ubiquitination, and acetylation [177][178][179][180][181][182][183]. These modifications lead to changes in c-Myb stability, DNA-binding activity and transcriptional transactivating activity.…”

Section: C-mybmentioning

confidence: 99%

“…Pim-1 can also phosphorylate undefined residues within the first 200 amino acids of c-Myb encompassing the DBD [189] to increase cMyb transcriptional transactivation activity [172]. c-Myb is acetylated in the conserved carboxyl-terminal lysine residues by p300 and CBP which increases DNA binding, transactivational activity, and affinity between c-Myb and CBP/p300 [173,179,190].…”

Section: C-mybmentioning

confidence: 99%

“…c-Myb also interacts with complexes that contain histone acetylases [173,174] and histone deacetylases [162] and c-Myb has the potential to affect gene expression based on the complex it interacts with. CREBbinding protein (CBP) and the related protein p300 are ubiquitously expressed histone acetyltransferases that bind to and acetylate c-Myb which increases its transcription transactivation activity [173][174][175]. CBP and p300 interact with RNA polymerase II and serve as a bridge between c-Myb and the basal transcriptional machinery to enhance the transcriptional activity of c-Myb [4,174,176].…”

Section: C-mybmentioning

confidence: 99%

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MYB IS Required for B-Selection During Thymopoises

Duley¹

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Abstractc-Myb is a transcription factor required during hematopoiesis and is crucial for multiple stages of thymopoiesis. Understanding c-Myb function during hematopoiesis has been greatly impeded due to the lack of a tractable genetic system. We have used the Cre/loxP approach to conditional mutagenesis to study c-Myb function during thymopoiesis. Thymocyte specific inactivation of the Myb locus demonstrated a block in DN3 to DN4 differentiation concomitant with impaired Vβ to DJβ recombination of the Tcrb locus suggesting that the inability to generate a TCRβ protein blocked DN3 differentiation. However, some DN3 thymocytes

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c-Myb acetylation at the carboxyl-terminal conserved domain by transcriptional co-activator p300

Cited by 118 publications

References 42 publications

Inhibition of cyclin A/Cdk2 phosphorylation impairs B-Myb transactivation function without affecting interactions with DNA or the CBP coactivator

Inhibition of cyclin A/Cdk2 phosphorylation impairs B-Myb transactivation function without affecting interactions with DNA or the CBP coactivator

Transcriptional Regulation by the Acetylation of Nonhistone Proteins in Humans – A New Target for Therapeutics

MYB IS Required for B-Selection During Thymopoises

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