Estrogen-responsive MYB gene expression

Stable Identifier
Reaction [omitted]
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

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
3498214 Differential expression of c-myb mRNA in murine B lymphomas by a block to transcription elongation

Bender, TP, Thompson, CB, Kuehl, WM

Science 1987
15276198 Cellular control of gene expression by T-type cyclin/CDK9 complexes

Garriga, J, Grana, X

Gene 2004
2181374 Strong association between c-myb and oestrogen-receptor expression in human breast cancer

Guérin, M, Sheng, ZM, Andrieu, N, Riou, G

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

Gaughan, L, Stockley, J, Coffey, K, O'Neill, D, Jones, DL, Wade, M, Wright, J, Moore, M, Tse, S, Rogerson, L, Robson, CN

Nucleic Acids Res. 2013
18476782 Estrogen and MYB in breast cancer: potential for new therapies

Gonda, TJ, Leo, P, Ramsay, RG

Expert Opin Biol Ther 2008
11034064 MYB oncogene amplification in hereditary BRCA1 breast cancer

Kauraniemi, P, Hedenfalk, I, Persson, K, Duggan, DJ, Tanner, M, Johannsson, O, Olsson, H, Trent, JM, Isola, J, Borg, A

Cancer Res. 2000
23435229 The lysine demethylase, KDM4B, is a key molecule in androgen receptor signalling and turnover

Coffey, K, Rogerson, L, Ryan-Munden, C, Alkharaif, D, Stockley, J, Heer, R, Sahadevan, K, O'Neill, D, Jones, D, Darby, S, Staller, P, Mantilla, A, Gaughan, L, Robson, CN

Nucleic Acids Res. 2013
17690249 Mechanism of and requirement for estrogen-regulated MYB expression in estrogen-receptor-positive breast cancer cells

Drabsch, Y, Hugo, H, Zhang, R, Dowhan, DH, Miao, YR, Gewirtz, AM, Barry, SC, Ramsay, RG, Gonda, TJ

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

Mitra, P, Pereira, LA, Drabsch, Y, Ramsay, RG, Gonda, TJ

Nucleic Acids Res. 2012
17013392 Genome-wide analysis of estrogen receptor binding sites

Carroll, JS, Meyer, CA, Song, J, Li, W, Geistlinger, TR, Eeckhoute, J, Brodsky, AS, Keeton, EK, Fertuck, KC, Hall, GF, Wang, Q, Bekiranov, S, Sementchenko, V, Fox, EA, Silver, PA, Gingeras, TR, Liu, XS, Brown, M

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

Frasor, J, Danes, JM, Komm, B, Chang, KC, Lyttle, CR, Katzenellenbogen, BS

Endocrinology 2003
20682797 The histone demethylase JMJD2B is regulated by estrogen receptor alpha and hypoxia, and is a key mediator of estrogen induced growth

Yang, J, Jubb, AM, Pike, L, Buffa, FM, Turley, H, Baban, D, Leek, R, Gatter, KC, Ragoussis, J, Harris, AL

Cancer Res. 2010
21445275 Histone demethylase JMJD2B functions as a co-factor of estrogen receptor in breast cancer proliferation and mammary gland development

Kawazu, M, Saso, K, Tong, KI, McQuire, T, Goto, K, Son, DO, Wakeham, A, Miyagishi, M, Mak, TW, Okada, H

PLoS ONE 2011
Participant Of
This event is regulated
Cite Us!