Retinoids, sex steroids and glucocorticoids regulate ectocervical cell envelope formation but not the level of the envelope precursor, involucrin

Gorodeski, George I.; Eckert, Richard L.; Utian, Wulf H.; Rorke, Ellen A.

doi:10.1111/j.1432-0436.1989.tb00609.x

Cited by 34 publications

(22 citation statements)

References 31 publications

(30 reference statements)

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“…2, zc-zf), but enhanced expression was seen again in superficial layers (Fig. 2, zc-zf), probably the result of trapped receptor in the superficial compact cells [cornified envelops (17); Fig. 2, ze].…”

Section: P2x 7 Protein Expressionmentioning

confidence: 99%

The P2X7 Receptor: A Novel Biomarker of Uterine Epithelial Cancers

Li¹,

Zhou²,

Feng

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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121

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Objective: To determine expression of the P2X 7 receptor in normal and in cancer uterine tissues. The rationale was that the receptor P2X 7 regulates constitutive apoptosis in uterine epithelial cells, and previous studies showed diminished P2X 7 -mediated apoptosis in cancer uterine cells compared with normal cells. Methods: A clinical, experimental feasibility study. Normal (n = 42) and cancer uterine tissues (n = 47) were obtained from a total of 72 women ages 25 to 75. End points for P2X 7 mRNA were quantitative PCR and in situ hybridization, and end points for P2X 7 protein were Western blots and immunostaining using anti-P2X 7 antibody. Results: (a) In normal uteri, P2X 7 mRNA and protein were expressed predominantly in the epithelial (endometrial, endocervical, and ectocervical) cells. (b) Expression of the P2X 7 mRNA and protein was absent from endometrial and endocervical adenocarcinoma tissues and from cervical squamous cell carcinoma tissues. (c) In cervical dysplasia, P2X 7 protein was absent in the dysplastic lesions. (d) Semiquantitative analysis using P2X 7 mRNA (normalized in each tissue to the constitutive glyceraldehyde-3-phosphate dehydrogenase) and P2X 7 protein levels (normalized in each tissue to the constitutive tubulin) revealed that P2X 7 mRNA and/or protein levels can distinguish uterine normal from cancer tissues at high degrees of sensitivity (92%, 100%) and specificity (100%, 90%). Summary and Conclusions: (a) Levels of the P2X 7 are lower in uterine epithelial cancer tissues than in the corresponding normal tissues. (b) The data suggest that tissue P2X 7 mRNA and protein levels could be used as a novel biomarker to differentiate normal and cancer uterine epithelial tissues. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1906 -13)

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Section: P2x 7 Protein Expressionmentioning

confidence: 99%

The P2X7 Receptor: A Novel Biomarker of Uterine Epithelial Cancers

Li¹,

Zhou²,

Feng

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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121

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“…After 4 days, the cells were harvested with Hanks' balanced salt solution containing 0.025% trypsin and 1 mM EDTA, fixed in isotonic buffer containing 4% formaldehyde, and counted using a Coulter counter. Cornified envelopes were counted as previously described (32,33).…”

Section: Fig 2 Hinv Promoter Sites That Mediate the Egcg Responsementioning

confidence: 99%

“…B, after EGCG treatment, the cells were harvested directly into Laemmli sample buffer and boiled (67). Cornified envelopes were counted as described previously (32,33). Values in parentheses indicate the ratio of the number of envelopes divided by the viable cell number expressed as a percentage.…”

Section: Fig 11 Egcg Enhances Cornified Envelope Formationmentioning

confidence: 99%

Green Tea Polyphenol Stimulates a Ras, MEKK1, MEK3, and p38 Cascade to Increase Activator Protein 1 Factor-dependent Involucrin Gene Expression in Normal Human Keratinocytes

Balasubramanian¹,

Efimova²,

Eckert³

2002

Journal of Biological Chemistry

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133

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(؊)-Epigallocatechin-3-gallate (EGCG) is an important bioactive constituent of green tea that efficiently reduces epidermal cancer cell proliferation. This inhibition is associated with a reduction in activator protein 1 (AP1) transcription factor level and activity. However, its effects on AP1 function in normal epidermal cells have not been extensively explored. Our present studies show that EGCG regulates normal keratinocyte function. To understand the mechanism of action, we examined the effects of EGCG on AP1 factor activity, MAPK signal transduction, and expression of the AP1 factorregulated human involucrin (hINV) gene. EGCG increases hINV promoter activity in a concentration-dependent manner that requires the presence of an intact hINV promoter AP1 factor binding site. This response appears to be physiologic, as endogenous hINV gene expression is also increased. Fra-1, Fra-2, FosB, JunB, JunD, c-Jun, and c-Fos levels are increased by EGCG treatment, as is AP1 factor binding to hINV promoter AP1 site. Gel mobility shift studies show that this complex contains Fra-1 and JunD. Signal transduction analysis indicates that the EGCG response requires Ras, MEKK1, MEK3, and p38 kinases. Kinase assays and inhibitor studies suggest that p38␦ is the p38 isoform responsible for the regulation. These changes are also associated with a cessation of cell proliferation and enhanced cornified envelope formation. These studies show that in normal human keratinocytes EGCG markedly increases, via a MAPK signaling mechanism, AP1 factor-associated responses.The polyphenol constituents of green tea inhibit carcinogenesis in a variety of tissues (1-4); however, their mechanism of action is not well understood. (Ϫ)-Epigallocatechin-3-gallate (EGCG) 1 is the major polyphenol isolated from green tea. AP1 transcription factors and AP1 factor-associated signal transduction are important targets of EGCG action (5-7). AP1 proteins consist of homodimers of Jun proteins (c-Jun, JunB, and JunD) and heterodimers of Jun and Fos (c-Fos, FosB, Fra-1, and Fra-2) factors (8). These proteins regulate transcription, differentiation, and cell proliferation by binding to specific recognition motifs in target genes (9 -13). EGCG produces specific changes in AP1 factor function in immortalized and transformed keratinocytes. These changes include an EGCGdependent reduction in phorbol ester-dependent mitogen-activated protein kinase (MAPK) activity (6), and reduced AP1 factor level and activity (7,14). EGCG also inhibits ultraviolet light-associated activation of c-Fos gene expression and the accumulation of c-Fos protein (7). Based on these studies, it has been suggested that the cancer-preventive role of EGCG may be due, in part, to its ability to reduce AP1 factor-related responses (6,7,14). However, very little information is available regarding how EGCG effects AP1 factor-regulated responses in normal keratinocytes. Our present studies show that EGCG increases AP1 factor levels in normal keratinocytes, and increases human involucrin gene expressio...

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“…However, it is not known whether ligands that interact selectively with the RAR or RXR or with specific subtypes within these families are more efficacious. Our previous studies show that naturally occurring retinoids, including all-trans-retinoic acid, suppress the growth of immortalized and transformed cervical cells, including ECE16-1 cells, while having no effect on normal cervical cell growth (2,12,38,39). Moreover, in some HPV-immortalized cells, t-RA inhibition of cell growth is associated with reduced HPV E6/E7 levels (40).…”

Section: Figmentioning

confidence: 99%

Retinoids Suppress Epidermal Growth Factor-associated Cell Proliferation by Inhibiting Epidermal Growth Factor Receptor-dependent ERK1/2 Activation

Sah¹,

Eckert²,

Chandraratna³

et al. 2002

Journal of Biological Chemistry

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Human papillomavirus (HPV) is an important etiological agent in the genesis of cervical cancer. HPV-positive cervical tumors and human papillomavirus-positive cell lines display increased epidermal growth factor receptor (EGFR) expression, which is associated with increased cell proliferation. ECE16-1 cells are an HPVimmortalized human ectocervical epithelial cell line that is a model of HPV-associated cervical neoplasia and displays elevated EGFR levels. In the present study, we evaluated the effects of receptor-selective retinoid ligands on EGFR-associated signal transduction. We show that retinoic acid receptor (RAR)-selective ligands reduce EGFR level and the magnitude and duration of EGFR activation in EGF-stimulated cells. These effects are reversed by cotreatment with an RAR antagonist. To identify the mechanism, we examined the effects of retinoid treatments on EGF-dependent signaling. Stimulation with EGF causes a biphasic activation of the ERK1/2 MAPK. The first peak of activation is present at 20 min, and the second is present at 36 h. This activation subsequently leads to an increase in the cyclin D1 level and increased cell proliferation. Simultaneous treatment with EGF and a RAR-selective retinoid inhibits both phases of ERK1/2 activation, completely eliminates the cyclin D1 induction, and suppresses EGF-dependent cell proliferation. This effect is specific as retinoid treatment does not alter the level or activity of other EGFRregulated kinases, including AKT and the MAPKs p38 and JNK. Retinoid X receptor-selective ligands, in contrast, did not regulate these responses. These results suggest that RAR ligand-associated down-regulation of EGFR activity reduces cell proliferation by reducing the magnitude and duration of EGF-dependent ERK1/2 activation.Retinoids are analogs of vitamin A that control cell growth and differentiation of a variety of epithelial tissues, including the lining of the uterine cervix (1, 2). Under conditions of retinoid deprivation, the normal mucus-producing cervical epithelium is converted to squamous-like metaplastic epithelium, a process that is reversed by readministration of vitamin A (3, 4). Both preneoplastic and dysplastic cervical lesions have been reported to revert to normal following retinoid treatment (5), suggesting that retinoids may be efficacious for the treatment of cervical disease (6).Human cervical cancer cells are characterized by the presence of the high risk forms of the human papillomavirus (7, 8). HPV16 1 is the predominant subtype (9). HPV encodes two oncogenes, E6 and E7, which immortalize cervical cells in culture, and are believed to play a key causal role, along with chemical mutagens, in the genesis of cervical cancer (10). Retinoid regulation of cervical cell function has been studied in both normal and HPV16-immortalized human cervical epithelial cells. These studies show that, at physiological levels, retinoids do not affect the growth of normal human ectocervical cells but markedly suppress the growth of HPV16-immortalized cells. Moreover,...

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Retinoids, sex steroids and glucocorticoids regulate ectocervical cell envelope formation but not the level of the envelope precursor, involucrin

Cited by 34 publications

References 31 publications

The P2X7 Receptor: A Novel Biomarker of Uterine Epithelial Cancers

The P2X7 Receptor: A Novel Biomarker of Uterine Epithelial Cancers

Green Tea Polyphenol Stimulates a Ras, MEKK1, MEK3, and p38 Cascade to Increase Activator Protein 1 Factor-dependent Involucrin Gene Expression in Normal Human Keratinocytes

Retinoids Suppress Epidermal Growth Factor-associated Cell Proliferation by Inhibiting Epidermal Growth Factor Receptor-dependent ERK1/2 Activation

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