Key roles for MED1 LxxLL motifs in pubertal mammary gland development and luminal-cell differentiation

Jiang, Pingping; Hu, Qian-Nan; Ito, Mitsuhiro; Meyer, Sara E.; Waltz, Susan E.; Khan, Sohaib A.; Roeder, Robert G.; Zhang, Xiaoting

doi:10.1073/pnas.1001814107

Cited by 72 publications

(105 citation statements)

References 44 publications

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“…The pups nursed by Med1 ϩ/Ϫ Med24 ϩ/Ϫ females grew normally, indicating that the mammary glands are functionally normal. These findings are reminiscent of the phenotype observed in Med1(LX) KI mice (19) and contrast with those of Med1 conditional KO mice (17). Taking into account that the alteration in Med1(LX) KI mammary glands apparently represents impaired ER␣ function, the phenotype of the Med1 ϩ/Ϫ Med24 ϩ/Ϫ mammary glands is also highly suggestive of impaired ER␣ function.…”

Section: Med1mentioning

confidence: 68%

“…To examine estradiol (E2)-stimulated mammary gland growth, 21-day-old virgin females were ovariectomized and implanted with 21-day slow-release pellets (0.025 mg; Innovative Research of America). After 21 days, inguinal glands were excised for whole-mount staining with carmine (Sigma) as described previously (19). All animal experiments were performed according to the institutional guidelines of the Animal Research Center, Kobe University, Japan.…”

Section: Methodsmentioning

confidence: 99%

“…For whole-mount staining, the inguinal mammary glands were isolated, fixed in Carnoy's fixative, and stained overnight in carmine alum (19). Samples were then cleared in xylene and mounted.…”

Section: Methodsmentioning

confidence: 99%

“…Hence, the attenuated function of the MED24-containing submodule might diminish the effect of MED1 and result in overtly altered phenotypes in circumstances where the dose of MED1 (or the MED24-containing submodule) is critical. This might be the case in mammary gland development particularly, as MED1 appears to be crucial in this process (17,19), and limited Med1 and/or Med24 gene doses in mice would reveal this hypothesis.…”

mentioning

confidence: 99%

“…Studies with mouse models using conditional knockout genes have shown that the MED1 subunit of the transcriptional Mediator is essential for both mammary gland development and lactation (17), while more recent genetic studies using LxxLL-mutant Med1 cDNA knock-in [Med1(LX) KI] mice showed that the contribution of direct interaction of MED1 with estrogen receptors is restricted to involvement in pubertal mammary gland development and luminal cell differentiation (19). The phenotypic differences in these studies suggest that, apart from its role as a nuclear receptor-specific coactivator, MED1 has yet-unidentified roles (probably through coactivation of other activators) in mammary gland physiology.…”

mentioning

confidence: 99%

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Mediator Subunits MED1 and MED24 Cooperatively Contribute to Pubertal Mammary Gland Development and Growth of Breast Carcinoma Cells

Hasegawa¹,

Sumitomo²,

Fujita³

et al. 2012

Molecular and Cellular Biology

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The Mediator subunit MED1 is essential for mammary gland development and lactation, whose contribution through direct interaction with estrogen receptors (ERs) is restricted to involvement in pubertal mammary gland development and luminal cell differentiation. Here, we provide evidence that the MED24-containing submodule of Mediator functionally communicates specifically with MED1 in pubertal mammary gland development. Mammary glands from MED1/MED24 double heterozygous knockout mice showed profound retardation in ductal branching during puberty, while single haploinsufficient glands developed normally. DNA synthesis of both luminal and basal cells were impaired in double mutant mice, and the expression of ERtargeted genes encoding E2F1 and cyclin D1, which promote progression through the G 1 /S phase of the cell cycle, was attenuated. Luciferase reporter assays employing double mutant mouse embryonic fibroblasts showed selective impairment in ER functions. Various breast carcinoma cell lines expressed abundant amounts of MED1, MED24, and MED30, and attenuated expression of MED1 and MED24 in breast carcinoma cells led to attenuated DNA synthesis and growth. These results indicate functional communications between the MED1 subunit and the MED24-containing submodule that mediate estrogen receptor functions and growth of both normal mammary epithelial cells and breast carcinoma cells. N uclear receptors, which include steroid and nonsteroid hormone receptors, comprise a superfamily of DNA-bound transcriptional regulators that are activated in response to specific small lipophilic ligands and that play major physiological roles in cell growth, differentiation, and homeostasis (reviewed in references 10 and 25). Estrogen receptor ␣ (ER␣) is the key activator that leads to growth of the mammary glands during adolescence, as well as during pregnancy, in response to elevated plasma estrogen levels. Among the hormone-responsive genes transcribed under the control of ER␣ is another steroid hormone receptor, progesterone receptor (PR), which in concert with ER␣, plays an important role in mammary gland development (5).The metazoan Mediator/TRAP coactivator complex is a master transcriptional coregulator composed of about 30 subunits and is structurally subdivided into head, body, and tail modules. It constitutes a subcomplex of the RNA polymerase II holoenzyme and integrates a wide variety of intracellular signals through specific interactions of activators with specific Mediator subunits that reside predominantly at its tail module (reviewed in references 4, 6, 15, 20, and 24). We have proposed a multistep model for nuclear receptor-induced transcriptional activation (15). In this model, histone-modifying coactivators that possess either histone acetyltransferase or histone methyltransferase activities first interact with ligand-bound nuclear receptors, and chromatin structure is subsequently relaxed. Then an exchange of coactivators takes place and the Mediator is bound to nuclear receptors through two canonical LxxLL nuc...

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Section: Med1mentioning

confidence: 68%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Mediator Subunits MED1 and MED24 Cooperatively Contribute to Pubertal Mammary Gland Development and Growth of Breast Carcinoma Cells

Hasegawa¹,

Sumitomo²,

Fujita³

et al. 2012

Molecular and Cellular Biology

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On the border of the homeotic function: Re‐evaluating the controversial role of cofactor‐recruiting motifs

Merabet¹,

Hudry²

2011

BioEssays

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In this review we present concepts that challenge a recently emerging paradigm explaining how similar Hox proteins perform different developmental functions across evolution, despite relatively limited sequence variability. This paradigm relates to the transcription factor, Fushi tarazu (Ftz), whose evolutionary plasticity has been shown to rely on the shuffling between two short protein recognition motifs. We discuss the Ftz paradigm and consider alternative interpretations to the evolutionary flexibility of this Hox protein. In particular, we propose that the protein environment might have played a critical role in the functional shuffling of Ftz during arthropod evolution.

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ftz Evolution: Findings, hypotheses and speculations (response to DOI 10.1002/bies.201100019)

Heffer¹,

Löhr²,

Pick³

2011

BioEssays

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In a recent paper, Merabet and Hudry discuss models explaining the functional evolution of fushi tarazu (ftz) from an ancestral homeotic to a pair-rule segmentation gene in Drosophila. As most of the experimental work underlying these models comes from our research, we wish to reply to Merabet and Hudry providing an explanation of the experimental approaches and logical framework underlying them. We review experimental data that support our hypotheses and discuss misconceptions in the literature. We emphasize that the change in ftz function required changes in both expression pattern and protein function and review the evidence that these functional changes involved a switch in cofactor-interaction motifs during arthropod radiations. While agreeing with Merabet and Hudry that protein context likely contributes to Ftz function, we argue that until supporting evidence for alternative mechanisms is obtained, the role of cofactor-interaction motifs in driving a functional switch remains compelling.

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Key roles for MED1 LxxLL motifs in pubertal mammary gland development and luminal-cell differentiation

Cited by 72 publications

References 44 publications

Mediator Subunits MED1 and MED24 Cooperatively Contribute to Pubertal Mammary Gland Development and Growth of Breast Carcinoma Cells

Mediator Subunits MED1 and MED24 Cooperatively Contribute to Pubertal Mammary Gland Development and Growth of Breast Carcinoma Cells

On the border of the homeotic function: Re‐evaluating the controversial role of cofactor‐recruiting motifs

ftz Evolution: Findings, hypotheses and speculations (response to DOI 10.1002/bies.201100019)

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