p300 is required for orderly G1/S transition in human cancer cells

Ng, Iyer; Jian, Xian; Chin, Suet-Feung; Bannister, Andrew J.; Daigo, Yataro; Aparicio, Samuel; Kouzarides, Tony; Caldas, Carlos

doi:10.1038/sj.onc.1209771

Cited by 54 publications

(57 citation statements)

References 33 publications

(55 reference statements)

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“…This is consistent with our previously published data showing that normal levels of both p300 and CBP are required for the repression of Myc in quiescent cells (Rajabi et al, 2005). In addition, published reports show that in vivo, these two proteins are present in limiting amounts and that they show dose-dependent effects on normal cell proliferation and development (Yao et al, 1998;Kung et al, 2000;Iyer et al, 2007).…”

Section: Discussionsupporting

confidence: 81%

p300 provides a corepressor function by cooperating with YY1 and HDAC3 to repress c-Myc

et al. 2008

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We showed earlier that p300/CBP plays an important role in G1 progression by negatively regulating c-Myc and thereby preventing premature G1 exit. Here, we have studied the mechanism by which p300 represses c-Myc and show that in quiescent cells p300 cooperates with histone deacetylase 3 (HDAC3) to repress transcription. p300 and HDAC3 are recruited to the upstream YY1-binding site of the c-Myc promoter resulting in chromatin deacetylation and repression of c-Myc transcription. Consistent with this, ablation of p300, YY1 or HDAC3 expression results in chromatin acetylation and induction of c-Myc. These three proteins exist as a complex in vivo and form a multiprotein complex with the YY1-binding site in vitro. The C-terminal region of p300 is both necessary and sufficient for the repression of c-Myc. These and other results suggest that in quiescent cells the C-terminal region of p300 provides corepressor function and facilitates the recruitment of p300 and HDAC3 to the YY1-binding site and represses the c-Myc promoter. This corepressor function of p300 prevents the inappropriate induction of c-Myc and S phase.

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Section: Discussionsupporting

confidence: 81%

p300 provides a corepressor function by cooperating with YY1 and HDAC3 to repress c-Myc

et al. 2008

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“…The structure of KIX ( Fig. 1) can be summarized as a three-helix bundle (α 1 , residues 597-611; α 2 , residues 623-640; α 3 , residues 646-669) containing a mobile L 12 -G 2 loop (residues 614-621) and an N-terminal 3 10 helix (residues 591-594). More importantly, KIX consists of at least two binding sites that are located on opposite surfaces of the protein, which can simultaneously bind, for example, the activation domain of the mixed lineage leukemia (MLL) protein and the activation domain of the protooncogene protein c-Myb (Fig.…”

mentioning

confidence: 99%

Prepaying the entropic cost for allosteric regulation in KIX

Law¹,

Gagnon²,

Mapp

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The kinase-inducible domain interacting (KIX) domain of the CREB binding protein (CBP) is capable of simultaneously binding two intrinsically disordered transcription factors, such as the mixedlineage leukemia (MLL) and c-Myb peptides, at isolated interaction sites. In vitro, the affinity for binding c-Myb is approximately doubled when KIX is in complex with MLL, which suggests a positive cooperative binding mechanism, and the affinity for MLL is also slightly increased when KIX is first bound by c-Myb. Expanding the scope of recent NMR and computational studies, we explore the allosteric mechanism at a detailed molecular level that directly connects the microscopic structural dynamics to the macroscopic shift in binding affinities. To this end, we have performed molecular dynamics simulations of free KIX, KIX-c-Myb, MLL-KIX, and MLL-KIX-c-Myb using a topology-based Go-like model. Our results capture an increase in affinity for the peptide in the allosteric site when KIX is prebound by a complementary effector and both peptides follow an effector-independent folding-and-binding mechanism. More importantly, we discover that MLL binding lowers the entropic cost for c-Myb binding, and vice versa, by stabilizing the L 12 -G 2 loop and the C-terminal region of the α 3 helix on KIX. This work demonstrates the importance of entropy in allosteric signaling between promiscuous molecular recognition sites and can inform the rational design of small molecule stabilizers to target important regions of conformationally dynamic proteins.

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“…Tab. 6 Occurrences of CRED-RA band types in samples from control groups and 4 mM EGTA-treated groups.…”

Section: Discussionmentioning

confidence: 99%

“…As the G1 progresses, pRB is sequentially hyperphosphorylated and inactivated: initially by early/mid-G1 CDKs (CDK6 and CDK4), and subsequently by late G1 CDKs (CDK2). Hyperphosphorylation of pRB releases E2F, which transactivates target genes that promote Sphase entry [6]. Other proteins engaged in G1/S transition include minichromosome…”

Section: Introductionmentioning

confidence: 99%

EGTA, a calcium chelator, affects cell cycle and increases DNA methylation in root tips of Triticum aestivum L.

Zhang

Shi

et al. 2016

Acta Soc Bot Pol

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In this study, when germinated Triticum aestivum L. seeds were treated with 0, 2, 4 and 6 mM ethyl glycol tetraacetic acid (EGTA), root growth was suppressed and the mitotic index decreased. These inhibitory effects were positively correlated with EGTA concentration. RT-PCR analysis revealed that the expression of several gene markers related to the G1/S transition of the cell cycle were significantly downregulated. Confocal microscopy of Fluo-3/AM-stained roots showed chelation of nearly all of the Ca 2+ within the root meristematic regions. Both random amplified polymorphic DNA (RAPD) and coupled restriction enzyme digestion-random amplification (CRED-RA) techniques showed significant increases in the levels of genomic DNA polymorphisms and degree of DNA methylation. The study provides information concerning the impact of Ca 2+ chelator, EGTA, on the growth, expression of cell cycle transition marker genes, and changes in DNA structure and methylation in the wheat roots.

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p300 is required for orderly G1/S transition in human cancer cells

Cited by 54 publications

References 33 publications

p300 provides a corepressor function by cooperating with YY1 and HDAC3 to repress c-Myc

p300 provides a corepressor function by cooperating with YY1 and HDAC3 to repress c-Myc

Prepaying the entropic cost for allosteric regulation in KIX

EGTA, a calcium chelator, affects cell cycle and increases DNA methylation in root tips of Triticum aestivum L.

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