Reversal of Bone Loss in Mice by Nongenotropic Signaling of Sex Steroids

Kousteni, Stavroula; Chen, J.-R.; Bellido, Teresita; Han, Li; Ali, Amjad; O’Brien, Charles A.; Plotkin, Lilian I.; Fu, Qiang; Mancino, Anne T.; Wen, Yufeng; Vertino, A. M.; Powers, Cara C.; Stewart, Scott A.; Ebert, Ray F.; Parfitt, A. M.; Weinstein, Robert S.; Jilka, Robert L.; Manolagas, Stavros C.

doi:10.1126/science.1074935

Cited by 387 publications

(142 citation statements)

References 18 publications

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“…Members of the steroid hormone family classically act through transcriptional regulation at the nuclear level (18). However, increasing evidence suggests that all of these hormones also exert rapid membrane-mediated effects on their target cells (2,(19)(20)(21)(22). Controversy exists regarding the identity of the membrane receptor proteins and specifically whether they are classical receptors or other binding proteins (6,8,9) Down-regulation of ER␣ by the selective siRNA in the present study clearly demonstrates the role of ER␣ itself in mediating the effects of E2 on MAPK activation.…”

Section: Discussionmentioning

confidence: 51%

The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor α to the plasma membrane

Song

Barnes

Zhang

et al. 2004

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

318

269

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Our previous studies demonstrated that 17␤-estradiol (E2) rapidly induces the interaction of estrogen receptor ␣ (ER␣) with the adapter protein Shc, the translocation of ER␣ to the cell membrane, and the formation of dynamic membrane structures in MCF-7 breast cancer cells. The present study examined how E2 causes ER␣ to translocate to the region of the plasma membrane and focused on mechanisms whereby Shc and the insulin-like growth factor-1 receptor (IGF-1R) mediate this process. Shc physically interacts with IGF-1R in the plasma membrane, and E2 activates IGF-1R. We reasoned that ER␣, when bound to Shc, would be directed to the region of the plasma membrane by the same processes, causing membrane translocation of Shc. We confirmed that E2 rapidly induced IGF-1R phosphorylation and demonstrated that E2 induced formation of a ternary protein complex among Shc, ER␣, and IGF-1R. Knock down of Shc with a specific small inhibitory RNA decreased the association of ER␣ with IGF-1R by 87%, suggesting that Shc is a crucial molecule in the formation of this ternary complex. Confocal microscopy studies provided further confirmation of the functional roles of Shc and the IGF-1R in the translocation of ER␣ to the region of the membrane. Down-regulation of Shc, ER␣, or IGF-1R with specific small inhibitory RNAs all blocked E2-induced mitogen-activated protein kinase phosphorylation. Together, our results demonstrate that Shc and IGF-1R serve as key elements in the translocation of ER␣ to the cell membrane and in the facilitation of ER␣-mediated rapid E2 action.

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Section: Discussionmentioning

confidence: 51%

The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor α to the plasma membrane

Song

Barnes

Zhang

et al. 2004

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

318

269

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“…DISCUSSION Although many studies focus on estrogen as an inhibitor of bone resorption, others suggest additional effects on bone formation. Recent evidence predicts that estrogen may act in part on osteoblasts to inhibit apoptosis (24 -27) or to regulate AP-1-related transcription factors by specific kinase-dependent pathways (25,27,57). In this report, we show that estradiol increases gene transactivation by Runx2, an essential transcription factor for skeletal tissue development (5,6).…”

Section: Fig 3 Er Associates With Runx2mentioning

confidence: 54%

Runx2 Integrates Estrogen Activity in Osteoblasts

McCarthy

Chang

Liu

et al. 2003

Journal of Biological Chemistry

108

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Steroids significantly effect skeletal integrity. For example, bone mass decreases with glucocorticoid excess or with estrogen depletion after menopause. Glucocorticoid suppresses gene expression by an essential skeletal tissue transcription factor, Runx2, in rat osteoblasts. We now report that estrogen enhances Runx2 activity in dose-and estrogen receptor-dependent ways independently of changes in Runx2 levels or its DNA binding potential. Estrogen receptor and Runx2 can be collected by co-immunoprecipitation. By two-hybrid gene expression analysis, high affinity complex formation involves portions of Runx2 outside of its own DNA binding domain and the DNA binding domain of the estrogen receptor. Consistent with this interaction, the stimulatory effect of estrogen on Runx2 activity is lost when the DNA binding domain of the estrogen receptor is eliminated. Unlike the stimulatory effect of estrogen and the inhibitory effect of glucocorticoid, androgen fails to increase Runx2 activity, whereas Runx2 potently suppresses gene expression induced by all three steroids. Finally, estrogen increases gene transcription by the transforming growth factor-␤ type I receptor gene promoter, which contains several Runx binding sequences, and enhances Smad dependent gene expression by transforming growth factor-␤ in osteoblasts. These results reveal that Runx2 can integrate complex effects on gene transcription in hormone-, growth factor-, and tissue-restricted ways.

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“…In light of these divergent effects, the identification of more selective ligands for the ER have been sought, ones that would retain the beneficial aspects of estrogen therapy, while eliminating the potentially harmful side effects. This goal has been accomplished with the tissue-selective estrogen, raloxifene, currently prescribed for the treatment of osteoporosis and demonstrated preclinically with the synthetic ER ligand, estren, working through a nongenotropic mechanism (38). Here, we describe the identification of a first-in-class pathwayselective ER ligand, specifically selective inflammatory modulators such as WAY-169916 that specifically antagonize NF-B transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%