Progesterone inhibits human endothelial cell proliferation through a p53-dependent pathway

Hsu, Sung Po; Ho, Pei Yin; Juan, Shu Hui; Liang, Yu Chih; Lee, W.-S.

doi:10.1007/s00018-008-8441-3

Cited by 25 publications

(23 citation statements)

References 34 publications

(34 reference statements)

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“…The p28-induced increase in p21 in MCF-7 cells was also accompanied by a time-dependent increase in p27, another member of the Cip/Kip CDK inhibitor family. Hsu et al (43) recently showed that induction of p53 increased both p21 and p27 promoter activity. In addition, p53 DNA-binding activity of the p21 and p27 promoters is reportedly activated by the p53 inducer, progesterone, suggesting that not only p21 but also p27 is transcriptionally regulated by p53 (43).…”

Section: Discussionmentioning

confidence: 99%

“…Hsu et al (43) recently showed that induction of p53 increased both p21 and p27 promoter activity. In addition, p53 DNA-binding activity of the p21 and p27 promoters is reportedly activated by the p53 inducer, progesterone, suggesting that not only p21 but also p27 is transcriptionally regulated by p53 (43). Collectively, our data suggest that enhancement of p53 levels subsequently upregulates p21 and p27, inducing a significant decrease in intracellular CDK2 and cyclin A levels in MCF-7 cells and inhibition of the cell cycle at G 2 -M (Fig.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A peptide fragment of azurin induces a p53-mediated cell cycle arrest in human breast cancer cells

Yamada

Mehta

Lekmine

et al. 2009

Molecular Cancer Therapeutics

149

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We report that amino acids 50 to 77 of azurin (p28) preferentially enter the human breast cancer cell lines MCF-7, ZR-75-1, and T47D through a caveolin-mediated pathway. Although p28 enters p53 wild-type MCF-7 and the isogenic p53 dominant-negative MDD2 breast cancer cell lines, p28 only induces a G 2 -M-phase cell cycle arrest and apoptosis in MCF-7 cells. p28 exerts its antiproliferative activity by reducing proteasomal degradation of p53 through formation of a p28:p53 complex within a hydrophobic DNA-binding domain (amino acids 80-276), increasing p53 levels and DNA-binding activity. Subsequent elevation of the cyclin-dependent kinase inhibitors p21 and p27 reduces cyclin-dependent kinase 2 and cyclin A levels in a time-dependent manner in MCF-7 cells but not in MDD2 cells. These results suggest that p28 and similar peptides that significantly reduce proteasomal degradation of p53 by a MDM2-independent pathway(s) may provide a unique series of cytostatic and cytotoxic (apoptotic) chemotherapeutic agents.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A peptide fragment of azurin induces a p53-mediated cell cycle arrest in human breast cancer cells

Yamada

Mehta

Lekmine

et al. 2009

Molecular Cancer Therapeutics

149

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“…To determine the protein-protein interaction, the immunoprecipitation assay was performed as previously described [10].…”

Section: Immunoprecipitationmentioning

confidence: 99%

“…The Matrigel angiogenesis assay was performed as previously [10,13]. A 500 lL portion of a liquid mixture of Matrigel (350 lL, BD Biosciences, CA), M199 medium (150 lL) and VEGF (50 ng/mL) with or without FA was injected subcutaneously into 7-week-old C57/BL6 male mice (8 mice in each group).…”

Section: Matrigel Angiogenesis Assaymentioning

confidence: 99%

Folic acid inhibits endothelial cell proliferation through activating the cSrc/ERK 2/NF-κB/p53 pathway mediated by folic acid receptor

Lin

Lee

et al. 2012

Angiogenesis

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Folate is important for normal cell division. Folate deficiency has been implicated in various diseases, including atherosclerosis, neural tube defects, and cancer. However, the effect of folate on angiogenesis was unclear. The aim of this study was to investigate the anti-angiogenic action of folic acid (FA). FA (0-10 μmol/L) concentration-dependently decreased DNA synthesis and proliferation in cultured human umbilical venous endothelial cells (HUVEC). Western blot analyses demonstrated that the levels of p21, p27 and p53 protein in HUVEC were increased by FA. The FA-inhibited [3H]thymidine incorporation was completely blocked when the expressions of p21 and p27 were knocked-down together. Knock-down of p53 prevented the FA-induced increases in p21 and p27 protein level. The levels of phosphorylated Src (p-Src) and p-Src-FA receptor (FR) complex in HUVEC were increased by FA. Knock-down of FR reduced the FA-induced increases of p-Src and p53. The FA-induced increases of p21, p27 and p53 protein levels were abolished when cSrc was knocked-down. FA also increased NF-κB nuclear translocation and binding onto the p53 promoter. The FA-induced up-regulation of the p53 promoter activity was prevented by knocked-down of ERK. Matrigel angiogenesis assay in mice demonstrate the anti-angiogenic effect of FA in vivo. In conclusion, our data indicate that FA bound to FR in HUVEC, subsequently activated the cSrc/ERK 2/NF-κB/p53 signaling pathway, which in turn up-regulated the expression of p21 and p27, and finally resulted in cell cycle arrest at the G0/G1 phase. In the present study, we uncover a completely novel role of FA for anti-angiogenesis.

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“…Progesterone has also shown several other beneficial effects on the vasculature. It protects against atherosclerosis by inhibiting smooth muscle proliferation in human and rat aortic smooth muscle cells (19,20), which may be mediated via a p53-dependent pathway (15). In ovariectomized rats with pulmonary hypertension, treatment with progesterone decreased the severity of hypertension, decreased vascular remodeling, and decreased mortality (45).…”

Section: Ajp-heart Circ Physiolmentioning

confidence: 99%

Short-term oral progesterone administration antagonizes the effect of transdermal estradiol on endothelium-dependent vasodilation in young healthy women

Miner

Martini

Smith

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Miner JA, Martini ER, Smith MM, Brunt VE, Kaplan PF, Halliwill JR, Minson CT. Short-term oral progesterone administration antagonizes the effect of transdermal estradiol on endotheliumdependent vasodilation in young healthy women. Am J Physiol Heart Circ Physiol 301: H1716 -H1722, 2011. First published August 19, 2011; doi:10.1152/ajpheart.00405.2011.-Very few studies have explored the cardiovascular effects of progesterone in premenopausal women. This study aimed to examine the short-term effects of oral progesterone alone, transdermal estrogen alone, and progesterone and estrogen combined on flow-mediated dilation (FMD) in healthy reproductive-aged women. We suppressed endogenous estrogens and progesterone in 17 premenopausal women for 10 -12 days using a gonadotropin-releasing hormone antagonist. On day 4 (hormone suppression condition), subjects were tested (n ϭ 17) and were then supplemented with either 200 mg micronized progesterone (n ϭ 8) orally or 0.1 mg estradiol (n ϭ 9) transdermally per day. On day 7 (progesterone-first or estradiol-first condition), subjects were tested and began supplementation with both hormones (n ϭ 17) and were tested again on day 10 (combined hormone condition). FMD of the brachial artery was assessed using B-mode arterial ultrasound, combined with synchronized Doppler analysis. As a result, significant differences in FMD were observed between hormone suppression (7.85 Ϯ 1.06%) and estrogen-first conditions (10.14 Ϯ 1.40%; P Ͻ 0.05). The estradiol-induced increase was abolished when oral progesterone was also supplemented (6.27 Ϯ 0.96%). In contrast, we observed a trend toward a decrease in FMD with unopposed progesterone administration, but no statistically significant differences were found between the progesterone-first (6.66 Ϯ 1.23%), hormone suppression (7.80 Ϯ 1.23%), and combined hormone conditions (7.40 Ϯ 1.29%). In conclusion, these data suggest that short-term oral micronized progesterone administration antagonizes the beneficial effect of transdermal estradiol on FMD.flow-mediated vasodilation; endothelial function; sex hormones; birth control WITH OVER 73% OF childbearing-aged women in the United States taking exogenous hormones for contraceptive and gynecological purposes (49a), the exploration of how exogenous hormones affect cardiovascular health is imperative. Although research on sex hormones has mainly focused on the effects of estrogens and manufactured progestins, there is relatively little known regarding the effect of progesterone on the vasculature. With progesterone production occurring naturally within the body and its bioidentical exogenous form being one of the most frequently prescribed progestogens, the need to understand the influence of progesterone on cardiovascular health is great.One of the primary methods used to investigate the effect of sex hormones on vascular health is via flow-mediated dilation (FMD). FMD, measured as the percent change in brachial artery diameter in response to an increase in shear stress, has been widely used as a nonin...

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Progesterone inhibits human endothelial cell proliferation through a p53-dependent pathway

Cited by 25 publications

References 34 publications

A peptide fragment of azurin induces a p53-mediated cell cycle arrest in human breast cancer cells

A peptide fragment of azurin induces a p53-mediated cell cycle arrest in human breast cancer cells

Folic acid inhibits endothelial cell proliferation through activating the cSrc/ERK 2/NF-κB/p53 pathway mediated by folic acid receptor

Short-term oral progesterone administration antagonizes the effect of transdermal estradiol on endothelium-dependent vasodilation in young healthy women

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