Estrogen-Induced Proliferation in Cultured Hepatocytes Involves Cyclin D1, P21CIP1 and P27KIP1

Barone, M.; Ladisa, R.; Leo, Alfredo Di; Spano, Daniela; Francioso, D.; Aglio, Veruska; Amoruso, A.; Francavilla, A.; Iolascon, Achille

doi:10.1007/s10620-006-3173-4

Cited by 9 publications

(4 citation statements)

References 34 publications

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“…In addition to regulating sex steroid hormones, hepatocytes express ER␣ and AR and respond to estrogens and androgens (21). For example, E2 has both proliferative and metabolic effects on hepatocytes in culture and in vivo (4,19,22). E2 has been shown to promote proliferation of male primary hepatocytes and hepatocellular carcinoma (HCC) cells in culture (4,19).…”

Section: Take Down Policymentioning

confidence: 99%

“…For example, E2 has both proliferative and metabolic effects on hepatocytes in culture and in vivo (4,19,22). E2 has been shown to promote proliferation of male primary hepatocytes and hepatocellular carcinoma (HCC) cells in culture (4,19). Studies have also suggested that increased estrogen levels may correlate with an increased risk of HCC in men and postmenopausal women (8,40).…”

Section: Take Down Policymentioning

confidence: 99%

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Cyclin D1 regulates hepatic estrogen and androgen metabolism

Mullany

Hanse

Romano³

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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Cyclin D1 is a cell cycle control protein that plays an important role in regenerating liver and many types of cancer. Previous reports have shown that cyclin D1 can directly enhance estrogen receptor activity and inhibit androgen receptor activity in a ligand-independent manner and thus may play an important role in hormone-responsive malignancies. In this study, we examine a distinct mechanism by which cyclin D1 regulates sex steroid signaling, via altered metabolism of these hormones at the tissue and cellular level. In male mouse liver, ectopic expression of cyclin D1 regulated genes involved in the synthesis and degradation of sex steroid hormones in a pattern that would predict increased estrogen and decreased androgen levels. Indeed, hepatic expression of cyclin D1 led to increased serum estradiol levels, increased estrogen-responsive gene expression, and decreased androgen-responsive gene expression. Cyclin D1 also regulated the activity of several key enzymatic reactions in the liver, including increased oxidation of testosterone to androstenedione and decreased conversion of estradiol to estrone. Similar findings were seen in the setting of physiological cyclin D1 expression in regenerating liver. Knockdown of cyclin D1 in HuH7 cells produced reciprocal changes in steroid metabolism genes compared with cyclin D1 overexpression in mouse liver. In conclusion, these studies establish a novel link between the cell cycle machinery and sex steroid metabolism and provide a distinct mechanism by which cyclin D1 may regulate hormone signaling. Furthermore, these results suggest that increased cyclin D1 expression, which occurs in liver regeneration and liver diseases, may contribute to the feminization seen in these settings.

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Section: Take Down Policymentioning

confidence: 99%

Section: Take Down Policymentioning

confidence: 99%

Cyclin D1 regulates hepatic estrogen and androgen metabolism

Mullany

Hanse

Romano³

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Phosphorylation on S118 of ERα is one such modification that can lead to tamoxifen resistance [51]. Cellular cycling influences the phosphorylation status of ERα in a manner that is dependent upon mitogen stimulation [25, 68]. In particular, phosphorylation on S118 is regulated by activated ERK1/2 [33, 34, 51].…”

Section: Discussionmentioning

confidence: 99%

The cyclin-like protein, SPY1, regulates the ERα and ERK1/2 pathways promoting tamoxifen resistance

Ferraiuolo

Tubman

Sinha³

et al. 2017

Oncotarget

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The Ras/Raf/MEK/ERK pathway conveys growth factor and mitogen signalling to control the phosphorylation of a plethora of substrates regulating proliferation, survival, and migration. The Ras signalling pathway is frequently associated with poor prognosis and drug resistance in various cancers including those of the blood, breast and prostate. Activation of the downstream effector ERK does not always occur via a linear cascade of events; complicating the targeting of this pathway therapeutically. This work describes a novel positive feedback loop where the cell cycle regulatory factor Spy1 (RINGO; gene SPDYA) activates ERK1/2 in a MEK-independent fashion. Spy1 was originally isolated for the ability to stimulate Xenopus oocyte maturation via a MAPK-signalling pathway and is known to override apoptosis triggered by the DNA damage response. We demonstrate that mammalian Spy1-mediated ERK activation increases ligand-independent phosphorylation and activation of estrogen receptor α, correlating with a decrease in tamoxifen sensitivity. This could define a novel druggable mechanism driving proliferation and resistance in select cancers.

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“…15 It has been previously shown that estrogen can act as a strong mitogen for hepatocytes and helps promote regeneration by increasing levels of cyclin D1 messenger RNA (mRNA) levels in hepatocytes. 16 Ovariectomized female rats given estrogen pellets showed a greater liver regeneration after portal branch ligation as compared to untreated ovariectomized female rats. 17 Similarly, the treatment of tamoxifen, an estrogen antagonist, to rats after partial hepatectomy (PHX) shows a decrease in hepatocyte proliferation.…”

Section: Introductionmentioning

confidence: 92%

Disruption of Estrogen Receptor Alpha in Rats Results in Faster Initiation of Compensatory Regeneration Despite Higher Liver Injury After Carbon Tetrachloride Treatment

et al. 2017

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Estrogen receptor alpha (ESR1) is one of the two intracellular receptors for estrogen and is expressed by hepatocytes in the liver. The role of ESR1 in the regulation of toxicant-induced liver injury and compensatory regeneration is not completely clear. We investigated the role of ESR1 in liver regeneration after carbon tetrachloride (CCl4)-induced liver injury using wild type (WT) and ESR1 knockout rats (ESR1-KO). Adult female WT and ESR1-KO rats were treated with 1ml/kg CCl4 and euthanized over a time course of 0–48 hr. Liver Injury measured by serum alanine amino transaminase (ALT) and histopathological analysis showed significantly higher liver injury in ESR1-KO as compared to WT rats. Hematoxylin and eosin (H&E) staining revealed two-fold higher necrosis and significant inflammatory cell infiltration in ESR1-KO rats. Chloracetate esterase staining revealed higher neutrophil infiltration in ESR1-KO rat livers. Interestingly, Proliferating cell nuclear antigen (PCNA) immunohistochemistry showed that in spite of two-fold higher liver injury, the ESR1KO rats had equal liver regeneration as compared to WT rats. Western blot analysis of cyclin D1 and phosphorylated Rb, proteins involved in the initiation of the cell cycle, were significantly higher at all time points in ESR1KO rats. Further analysis revealed faster activation of canonical Wnt/β-catenin and NF-κB signaling in ESR1-KO rats characterized by higher activated β-catenin and phosphorylated p65 at 12 hr after CCl4 treatment. Taken together, these data indicate that ESR1-mediated signaling inhibits liver regeneration by down regulation of Wnt signaling resulting in lower cyclin D1 activation after chemical-induced liver injury.

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Estrogen-Induced Proliferation in Cultured Hepatocytes Involves Cyclin D1, P21CIP1 and P27KIP1

Cited by 9 publications

References 34 publications

Cyclin D1 regulates hepatic estrogen and androgen metabolism

Cyclin D1 regulates hepatic estrogen and androgen metabolism

The cyclin-like protein, SPY1, regulates the ERα and ERK1/2 pathways promoting tamoxifen resistance

Disruption of Estrogen Receptor Alpha in Rats Results in Faster Initiation of Compensatory Regeneration Despite Higher Liver Injury After Carbon Tetrachloride Treatment

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