Inhibition of proliferation and expression of T1 and cyclin D1 genes by thyroid hormone in mammary epithelial cells

2002 ◽  
Vol 34 (1) ◽  
pp. 25-34 ◽  
Author(s):  
José Manuel González-Sancho ◽  
Angélica Figueroa ◽  
Mónica López-Barahona ◽  
Eva López ◽  
Hartmut Beug ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Epithelial Cells ◽  
Cyclin D1 ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Inhibition Of Proliferation

scholarly journals PIN1 Is an E2F Target Gene Essential for Neu/Ras-Induced Transformation of Mammary Epithelial Cells

2002 ◽  
Vol 22 (15) ◽  
pp. 5281-5295 ◽  
Author(s):  
Akihide Ryo ◽  
Yih-Cherng Liou ◽  
Gerburg Wulf ◽  
Masafumi Nakamura ◽  
Sam W. Lee ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cyclin D1 ◽  
Transcriptional Activation ◽  
Target Gene ◽  
Mammary Epithelial Cells ◽  
Cell Transformation ◽  
Mammary Tumorigenesis ◽  
Mammary Epithelial ◽  
Oncogenic Signaling ◽  
And Function

ABSTRACT Oncogenes Neu/HER2/ErbB2 and Ras can induce mammary tumorigenesis via upregulation of cyclin D1. One major regulatory mechanism in these oncogenic signaling pathways is phosphorylation of serines or threonines preceding proline (pSer/Thr-Pro). Interestingly, the pSer/Thr-Pro motifs in proteins exist in two completely distinct cis and trans conformations, whose conversion is catalyzed specifically by the essential prolyl isomerase Pin1. By isomerizing pSer/Thr-Pro bonds, Pin1 can regulate the conformation and function of certain phosphorylated proteins. We have previously shown that Pin1 is overexpressed in breast tumors and positively regulates cyclin D1 by transcriptional activation and posttranslational stabilization. Moreover, in Pin1 knockout mice, mammary epithelial cells fail to undergo massive proliferation during pregnancy, as is the case in cyclin D1 null mice. These results indicate that Pin1 is upregulated in breast cancer and may be involved in mammary tumors. However, the mechanism of Pin1 overexpression in cancer and its significance in cell transformation remain largely unknown. Here we demonstrate that PIN1 expression is mediated by the transcription factor E2F and enhanced by c-Neu and Ha-Ras via E2F. Furthermore, overexpression of Pin1 not only confers transforming properties on mammary epithelial cells but also enhances the transformed phenotypes of Neu/Ras-transformed mammary epithelial cells. In contrast, inhibition of Pin1 suppresses Neu- and Ras-induced transformed phenotypes, which can be fully rescued by overexpression of a constitutively active cyclin D1 mutant that is refractory to the Pin1 inhibition. Thus, Pin1 is an E2F target gene that is essential for the Neu/Ras-induced transformation of mammary epithelial cells through activation of cyclin D1.

scholarly journals The Ras oncogene signals centrosome amplification in mammary epithelial cells through cyclin D1/Cdk4 and Nek2

Oncogene ◽  
2010 ◽  
Vol 29 (36) ◽  
pp. 5103-5112 ◽  
Author(s):  
X Zeng ◽  
F Y Shaikh ◽  
M K Harrison ◽  
A M Adon ◽  
A J Trimboli ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cyclin D1 ◽  
Mammary Epithelial Cells ◽  
Centrosome Amplification ◽  
Mammary Epithelial ◽  
Ras Oncogene

Activation of G Protein-coupled Receptor 30 Promotes Proliferation of Goat Mammary Epithelial Cells via MEK/Erk&PI3K/Akt Signaling Pathway

2020 ◽  
Author(s):  
Ying Zhao ◽  
Haokun Liu ◽  
Mingzhen Fan ◽  
Yuyang Miao ◽  
Xiaoe Zhao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Epithelial Cells ◽  
Cyclin D1 ◽  
Mammary Epithelial Cells ◽  
Cyclin B1 ◽  
Akt Signaling ◽  
Mammary Epithelial ◽  
M Phase ◽  
G Protein Coupled ◽  
Goat Mammary Epithelial Cells

Abstract BackgroundGoat is an important dairy animal. During lactation, maintaining a high proliferative activity in goat mammary epithelial cells (GMECs) is significant to improve the yield and composition of goat milk. Estrogen is an essential hormone in epithelial cell proliferation and ductal morphogenesis of mammary gland. G protein-coupled receptor 30 (GPR30) is a novel membrane receptor of estrogen. However, the relationship between estrogen/GPR30 signaling and proliferation of goat mammary epithelial cells has not been reported. And the molecular mechanisms underlying the proliferative effect of estrogen via GPR30 on GMECs remain unclear.ResultsTo investigate the effect of estrogen/GPR30 signaling on GMECs proliferation, goat mammary epithelial cells, which expressed cytokeratin 18 and β-casein, were isolated and identified, defining their mammary alveolar epithelium origination. Estrogen and GPR30 agonist G1 obviously promoted the proliferation of GEMCs, in contrast, GPR30 antagonist G15 partly abolished estrogen-induced cell proliferation. Remarkably, the stimulatory effect of estrogen and G1 on GMECs growth was suppressed by GPR30 knockdown detected by cell counting assay, CCK-8 assay, and BrdU assay, suggesting that estrogen/GPR30 signaling was involved in GMECs proliferation. Additionally, G15 decreased cyclin D1, cyclin B1, CDK1, and p-CDK1 expression, resulting in cell cycle arrest in the G2/M phase via a down-regulated phosphorylation of Erk1/2 and Akt compared with estrogen alone. What’s more, knock-down GPR30 led to an accumulation in the G2/M phase and inhibition of cyclin D1, cyclin B1, CDK1, and p-CDK1 expression via a down-regulation of phosphorylated Erk1/2 and Akt despite the presence of estrogen and G1. Furthermore, MEK inhibitor and PI3K inhibitor decreased the expression of cyclin D1, cyclin B1, CDK1, and p-CDK1, and repressed estrogen-induced and G1-driven promotion of cell growth. It indicated that estrogen/GPR30 signaling played an important role in GMECs proliferation by affecting cell cycle progression via MEK/Erk&PI3K/Akt signaling pathway.ConclusionThis study may provide a new insight into the effect of estrogen/GPR30 signaling on the regulatory action of goat mammary gland development.

scholarly journals Rho regulates p21CIP1, cyclin D1, and checkpoint control in mammary epithelial cells

Oncogene ◽  
2002 ◽  
Vol 21 (10) ◽  
pp. 1590-1599 ◽  
Author(s):  
Muriel Liberto ◽  
David Cobrinik ◽  
Audrey Minden
Keyword(s):  
Epithelial Cells ◽  
Cyclin D1 ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Checkpoint Control

scholarly journals NFκB1/p50 Is Not Required for Tumor Necrosis Factor-Stimulated Growth of Primary Mammary Epithelial Cells: Implications for NFκB2/p52 and RelB

Endocrinology ◽  
2007 ◽  
Vol 148 (1) ◽  
pp. 268-278 ◽  
Author(s):  
Jiping Zhang ◽  
Mary Ann Warren ◽  
Suzanne F. Shoemaker ◽  
Margot M. Ip
Keyword(s):  
Dna Binding ◽  
Epithelial Cells ◽  
Cyclin D1 ◽  
Mammary Epithelial Cells ◽  
Three Dimensional ◽  
Nuclear Factor Κb ◽  
Mammary Epithelial ◽  
Wild Type ◽  
Nuclear Extracts ◽  
Dna Binding Complexes

Nuclear factor κB (NFκB) plays an important role in mammary gland development and breast cancer. We previously demonstrated that TNF stimulates growth of mammary epithelial cells (MEC) in a physiologically relevant three-dimensional primary culture system, accompanied by enhanced DNA-binding of the NFκB p50 homodimer. To further understand the mechanism of TNF-stimulated growth of primary MEC, the requirement for NFκB1/p50, and the role of cyclin D1 in TNF-stimulated growth were examined. TNF induced the formation of DNA-binding complexes of p50 and p52 with their coactivator bcl3 in MEC nuclear extracts. Concomitantly, TNF increased the binding of NFκB proteins to the κB site on the cyclin D1 promoter, and increased expression of cyclin D1 mRNA and protein. Using MEC from p50 null mice, we found that p50 was not required for TNF-induced growth nor for up-regulation of cyclin D1. However, TNF induced a p52/RelB NFκB DNA-binding complex in p50 null MEC nuclear extracts. In addition, we found that in wild-type MEC, TNF stimulated the occupancy of p52 and RelB on the cyclin D1 promoter κB site, whereas p50 was present constitutively. These data suggest that in wild-type MEC, TNF stimulates the interaction of bcl3 with p50 and p52, and the binding of p52, as well as RelB, to cyclin D1 promoter κB sites, and as a consequence, stimulates the growth of MEC. In the absence of p50, p52 and RelB can compensate for p50 in TNF-stimulated growth and cyclin D1 induction in MEC.

scholarly journals ErbB2/Neu-Induced, Cyclin D1-Dependent Transformation Is Accelerated in p27-Haploinsufficient Mammary Epithelial Cells but Impaired in p27-Null Cells

2002 ◽  
Vol 22 (7) ◽  
pp. 2204-2219 ◽  
Author(s):  
Rebecca S. Muraoka ◽  
Anne E. G. Lenferink ◽  
Brian Law ◽  
Elizabeth Hamilton ◽  
Dana M. Brantley ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cyclin D1 ◽  
Nuclear Localization ◽  
Nuclear Export ◽  
Mammary Epithelial Cells ◽  
Cell Transformation ◽  
Mammary Epithelium ◽  
Tumor Formation ◽  
Mammary Epithelial ◽  
Cdk4 Activity

ABSTRACT ErbB2/Neu destabilizes the cyclin-dependent kinase (Cdk) inhibitor p27 and increases expression of cyclin D1. Therefore, we studied the roles of p27 and cyclin D1 in ErbB2-mediated mammary epithelial cell transformation. Overexpression of ErbB2 or cyclin D1 in p27+/− primary murine mammary epithelial cells resulted in increased proliferation, cyclin D1 nuclear localization, and colony formation in soft agar compared to those in p27+/+ cells. In contrast, ErbB2- or cyclin D1-overexpressing p27−/− cells displayed reduced proliferation, anchorage-independent growth, Cdk4 activity, cyclin D1 expression, and cyclin D1 nuclear localization compared to wild-type cells. A cyclin D1 mutation in its nuclear export sequence (T286A) partially rescued nuclear localization of cyclin D1 in p27−/− cells but did not increase proliferation or Cdk4 kinase activity. Overexpression of E2F1, however, increased proliferation to the same degree in p27+/+ , p27+/− , and p27−/− cells. Mammary glands from MMTV (mouse mammary tumor virus)-neu/p27+/− mice exhibited alveolar hyperplasia, enhanced proliferation, decreased apoptosis, and accelerated tumor formation compared to MMTV-neu/p27+/+ glands. However, MMTV-neu/p27−/− glands showed decreased proliferation, cyclin D1 expression, and Cdk4 activity, as well as markedly prolonged tumor latency, compared to MMTV-neu/p27+/+ glands. These results suggest that p27+/− mammary epithelium may be more susceptible to oncogene-induced tumorigenesis, whereas p27-null glands, due to severely impaired cyclin D1/Cdk4 function, are more resistant to transformation.

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