6mnl

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NMR solution structures of second bromodomain of BRD4 with FOXO3a peptide

Structural highlights

6mnl is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

FOXO3_HUMAN Note=A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with MLL/HRX.

Function

FOXO3_HUMAN Transcriptional activator which triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress. Recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3'. Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation.^[1] ^[2] ^[3]

Publication Abstract from PubMed

BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or CDK6 significantly overcomes the resistance of luminal breast cancer cells to AKT inhibitors in vitro and in vivo. Our study reports the involvement of BRD4/FOXO3a/CDK6 axis in AKTi resistance and provides potential therapeutic strategies for treating resistant breast cancer.

Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer.,Liu J, Duan Z, Guo W, Zeng L, Wu Y, Chen Y, Tai F, Wang Y, Lin Y, Zhang Q, He Y, Deng J, Stewart RL, Wang C, Lin PC, Ghaffari S, Evers BM, Liu S, Zhou MM, Zhou BP, Shi J Nat Commun. 2018 Dec 5;9(1):5200. doi: 10.1038/s41467-018-07258-y. PMID:30518851^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999 Mar 19;96(6):857-68. PMID:10102273
↑ Lehtinen MK, Yuan Z, Boag PR, Yang Y, Villen J, Becker EB, DiBacco S, de la Iglesia N, Gygi S, Blackwell TK, Bonni A. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell. 2006 Jun 2;125(5):987-1001. PMID:16751106 doi:S0092-8674(06)00559-9
↑ Kress TR, Cannell IG, Brenkman AB, Samans B, Gaestel M, Roepman P, Burgering BM, Bushell M, Rosenwald A, Eilers M. The MK5/PRAK kinase and Myc form a negative feedback loop that is disrupted during colorectal tumorigenesis. Mol Cell. 2011 Feb 18;41(4):445-57. doi: 10.1016/j.molcel.2011.01.023. PMID:21329882 doi:10.1016/j.molcel.2011.01.023
↑ Liu J, Duan Z, Guo W, Zeng L, Wu Y, Chen Y, Tai F, Wang Y, Lin Y, Zhang Q, He Y, Deng J, Stewart RL, Wang C, Lin PC, Ghaffari S, Evers BM, Liu S, Zhou MM, Zhou BP, Shi J. Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer. Nat Commun. 2018 Dec 5;9(1):5200. doi: 10.1038/s41467-018-07258-y. PMID:30518851 doi:http://dx.doi.org/10.1038/s41467-018-07258-y