Reactome | Estrogen-responsive MYB gene expression

Estrogen-responsive MYB gene expression

Stable Identifier

R-HSA-9011971

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

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MYB is frequently expressed in breast cancer and its expression is correlated with ER positive tumors (Guerin et al, 1990; Kauraniemi et al, 2000). MYB expression is estrogen-responsive, but hormone-dependent control is exerted at the level of transcriptional elongation rather than initiation (Frasor et al, 2003; Carroll et al, 2006; Bender et al, 1987; Watson et al, 1988; Drabsch et al, 2007). In the absence of estrogen, RNA polymerase II stalls at a stem-loop poly-T (SL-dT) tract between within intron 1 (Drabsch et al, 2007). Upon estrogen stimulation, a complex containing estrogen, the estrogen receptor and P-TEFb (an elongation factor consisting of Cyclin T and CDK9) is recruited to an ERE near the SL-dT. P-TEFb phosphorylates serine 2 in the RNA polymerase II CTD, allowing the polymerase to continue elongating (Drabsch et al, 2007; Mitra et al, 2012; reviewed in Gonda et al, 2008; Garriga and Grana, 2004). Although EREs have been identified around the SL-dT and have been shown by ChIP to be bound by ESR1, mutation of the EREs does not abrogate estrogen-responsive MYB expression, suggesting that the estrogen receptor either binds to a non-canonical site or it interacts through another transcription factor in this reaction (Drabsch et al, 2007; Mitra et al, 2012).
Transcriptional induction of MYB is also dependent on KDM4B-dependent H3K9 promoter/enhancer demethylation. KDM4B interacts with ESR1 and is recruited to estrogen-responsive target gene promoters or enhancers in an estrogen-dependent manner (Kawazu et al, 2011; Gaughan et al, 2013). Depletion of KDM4B in T47D and MCF7 breast cancer cell lines abrogates the proliferative response to estrogen, consistent with its role in driving expression of estrogen-dependent cell cycle regulators like MYC and CCND1 (Kawazu et al, 2011; Yang et al, 2010). KDM4B additionally interacts with the transcriptional activator SMARCA4, and depletion of KDM4B compromises the recruitment of RNA polymerase II to the MYB promoter in T47D cells (Kawazu et al, 2011). KDM4B is highly expressed in ER alpha-positive breast cancer and prostate cancer (Gaughan et al, 2013; Coffey et al, 2013). KDM4B may also promote estrogen-responsive signaling by interacting with GATA3 and binding to the enhancers of ESR1and FOXA1 genes (Gaughan et al, 2013). How and when (or whether) KDM4B interacts with P-TEFb has not been examined.

Literature References

PubMed ID	Title	Journal	Year
15276198	Cellular control of gene expression by T-type cyclin/CDK9 complexes Grana, X, Garriga, J	Gene	2004
3498214	Differential expression of c-myb mRNA in murine B lymphomas by a block to transcription elongation Thompson, CB, Bender, TP, Kuehl, WM	Science	1987
2181374	Strong association between c-myb and oestrogen-receptor expression in human breast cancer Guérin, M, Sheng, ZM, Riou, G, Andrieu, N	Oncogene	1990
3281094	A transcriptional arrest mechanism involved in controlling constitutive levels of mouse c-myb mRNA Watson, RJ	Oncogene	1988
23723241	KDM4B is a master regulator of the estrogen receptor signalling cascade Wade, M, O'Neill, D, Gaughan, L, Stockley, J, Tse, S, Robson, CN, Moore, M, Coffey, K, Rogerson, L, Jones, DL, Wright, J	Nucleic Acids Res.	2013
18476782	Estrogen and MYB in breast cancer: potential for new therapies Leo, P, Gonda, TJ, Ramsay, RG	Expert Opin Biol Ther	2008
11034064	MYB oncogene amplification in hereditary BRCA1 breast cancer Persson, K, Kauraniemi, P, Trent, JM, Duggan, DJ, Hedenfalk, I, Johannsson, O, Borg, A, Tanner, M, Isola, J, Olsson, H	Cancer Res.	2000
23435229	The lysine demethylase, KDM4B, is a key molecule in androgen receptor signalling and turnover Jones, D, Heer, R, Alkharaif, D, Gaughan, L, Stockley, J, Mantilla, A, Coffey, K, Ryan-Munden, C, Rogerson, L, Darby, S, Sahadevan, K, Staller, P, O'Neill, D, Robson, CN	Nucleic Acids Res.	2013
17690249	Mechanism of and requirement for estrogen-regulated MYB expression in estrogen-receptor-positive breast cancer cells Barry, SC, Miao, YR, Drabsch, Y, Gonda, TJ, Dowhan, DH, Ramsay, RG, Gewirtz, AM, Hugo, H, Zhang, R	Proc. Natl. Acad. Sci. U.S.A.	2007
22492511	Estrogen receptor-α recruits P-TEFb to overcome transcriptional pausing in intron 1 of the MYB gene Pereira, LA, Drabsch, Y, Mitra, P, Gonda, TJ, Ramsay, RG	Nucleic Acids Res.	2012
17013392	Genome-wide analysis of estrogen receptor binding sites Bekiranov, S, Hall, GF, Li, W, Fertuck, KC, Geistlinger, TR, Sementchenko, V, Liu, XS, Brodsky, AS, Meyer, CA, Silver, PA, Fox, EA, Brown, M, Wang, Q, Keeton, EK, Eeckhoute, J, Song, J, Gingeras, TR, Carroll, JS	Nat. Genet.	2006
12959972	Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype Chang, KC, Lyttle, CR, Katzenellenbogen, BS, Frasor, J, Komm, B, Danes, JM	Endocrinology	2003
20682797	The histone demethylase JMJD2B is regulated by estrogen receptor alpha and hypoxia, and is a key mediator of estrogen induced growth Buffa, FM, Turley, H, Ragoussis, J, Gatter, KC, Pike, L, Leek, R, Baban, D, Harris, AL, Jubb, AM, Yang, J	Cancer Res.	2010
21445275	Histone demethylase JMJD2B functions as a co-factor of estrogen receptor in breast cancer proliferation and mammary gland development Okada, H, McQuire, T, Goto, K, Mak, TW, Miyagishi, M, Son, DO, Saso, K, Kawazu, M, Wakeham, A, Tong, KI	PLoS ONE	2011