The human involucrin gene contains spatially distinct regulatory elements that regulate expression during early versus late epidermal differentiation

Crish, James F.; Bone, Frederic; Banks, Eric B.; Eckert, Richard L.

doi:10.1038/sj.onc.1205038

Cited by 41 publications

(54 citation statements)

References 44 publications

(43 reference statements)

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“…ΔΝp63α has been reported to play a role in normal epithelial cell di erentiation, and involucrin is an early di erentiation marker for the keratinocytes of the epidermis [13]. us, the expression levels of ΔΝp63α were further explored in both normal cervical tissues and cervical cancer tissues using involucrin as a marker.…”

Section: δν αmentioning

confidence: 99%

Reduced expression of ΔΝp63α in cervical squamous cell carcinoma

Ying¹,

Xu²,

Ling³

et al. 2011

CIM

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Reduced expression of ΔΝp63α in cervical squamous cell carcinoma Abstract Purpose: As a member of the p53 family, p63 is considered to be an important di erentiation regulation transcriptional factor, but the roles of p63 in many epithelial tumourigenesis and metastasis processes are still not clear. is study was designed to investigate the expression of p63 and its isoform in normal tissues and squamous cell cancer tissues of uterine cervix, and its signi cance in cancer cell di erentiation.Methods: e expression of p63 was assessed in cervical tissue and cell lines by immunohistochemistry, RT-PCR and Western Blotting. e relationships between p63 protein, various clinico-pathological features, and the di erentiation marker involucrin were analyzed.Results: ΔΝp63α is the predominant isoform expressed in cervical epithelial tissues, and it is decreased in moderately or poorly di erentiated cervical squamous carcinoma, as well as in the HeLa, SiHa and C33A cervical cancer cell lines. e expression level of ΔΝp63α was positively correlated with that of involucrin in cervical squamous cancer tissue, and the expression of ΔΝp63α is decreased with the degree of tumour invasion.Conclusion: e decrease of ΔΝp63α in cervical squamous cell cancer appears to be associated with the tumour progression, and ΔΝp63α may be a sensitive marker for cervical squamous cancer di erentiation.

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Section: δν αmentioning

confidence: 99%

Reduced expression of ΔΝp63α in cervical squamous cell carcinoma

Ying¹,

Xu²,

Ling³

et al. 2011

CIM

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“…Keratinocyte differentiating agents, including calcium and phorbol ester, activate involucrin gene expression Efimova et al, 2002;Efimova et al, 2003) via a signaling cascade that includes the novel PKC isoforms (nPKC), Ras, MEKK1, and MEK3 (Agarwal et al, 1999;Welter et al, 1995;Efimova and Eckert, 2000;Efimova et al, 1998). Activation of this cascade leads to an increase in p38δ and a decrease in ERK1/2 activity leading to an increase in the levels of AP1, Sp1 and CAATT enhancer binding protein (C/EBP) expression, increased binding of these factors to the hINV promoter, and increased hINV gene expression (Banks et al, 1998;Welter et al, 1995;Crish et al, 2002). Evidence for this cascade is provided by studies using pharmacological agents, constitutively-active and dominant-negative kinases, and kinase assays (Efimova and Eckert, 2000;Efimova et al, 1998;Efimova et al, 2002;Efimova et al, 2003).…”

mentioning

confidence: 99%

“…Evidence for this cascade is provided by studies using pharmacological agents, constitutively-active and dominant-negative kinases, and kinase assays (Efimova and Eckert, 2000;Efimova et al, 1998;Efimova et al, 2002;Efimova et al, 2003). As a model to study the impact of dietary agents on keratinocyte function, we have studied the impact of a range of antioxidants on expression of involucrin (Crish et al, 1993;Crish et al, 1998;Crish et al, 2002;Eckert et al, 2004). We have also examined the impact of treatment with chemopreventive agents on keratinocyte proliferation and apoptosis.…”

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confidence: 99%

Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

Balasubramanian

Eckert

2007

Toxicology and Applied Pharmacology

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We have proposed that it is important to examine the impact of chemopreventive agents on the function of normal human epidermal keratinocytes, since these cells comprise the barrier that protects the body from a range of environmental insults. In this context, it is widely appreciated that cancer may be retarded by consumption or topical application of naturally-occurring food-derived chemopreventive agents. Our studies show that (−)-epigallocatechin-3-gallate (EGCG), a green teaderived polyphenol, acts to enhance the differentiation of normal human keratinocytes as evidenced by its ability to increase involucrin (hINV), transglutaminase type 1 (TG1) and caspase-14 gene expression. EGCG also stimulates keratinocyte morphological differentiation. These actions of EGCG are mediated via activation of a nPKC, Ras, MEKK1, MEK3, p38δ-ERK1/2 signaling cascade which leads to increased activator protein 1 (AP1) and CAATT enhancer binding protein (C/EBP) transcription factor expression, increased binding of these factors to DNA, and increased gene transcription. In contrast, apigenin, a dietary flavonoid derived from plants and vegetables, and curcumin, an agent derived from turmeric, inhibit differentiation by suppressing MAPK signal transduction and reducing API transcription factor level. Curcumin also acts to enhance apoptosis, although EGCG and apigenin do not stimulate apoptosis. In addition, all of these agents inhibit keratinocyte proliferation. These findings indicate that each of these diet-derived chemopreventive agents has a profound impact on normal human keratinocyte function and that they operate via distinct and sometimes opposing mechanisms. However, all are expected to act as chemopreventive agents. KeywordsEGCG; apigenin; curcumin; TPA; epidermis; involucrin; keratinocyte differentiation; apoptosis; chemoprevention; turmeric Keratinocyte differentiation and human involucrin gene expressionThe keratinocyte is the major cell type of the multilayered stratified squamous epithelium (the epidermis) that covers the body surface. To establish epidermal structure, keratinocytes in the basal layer undergo periodic cell division which gives rise to daughter cells that differentiate

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“…During the late stages of differentiation, involucrin is crosslinked with proteins and lipids to form cornified cell envelopes in the uppermost cells of stratified epithelia (Eckert and Welter, 1996). Five AP-1 consensus sites exist in the promoter region of the involucrin gene with two sites accounting for 80% of promoter activity (Crish et al, 2002). One site is proximal while the other is distal to the transcription start site.…”

mentioning

confidence: 99%

Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas

Azuma

et al. 2004

Br J Cancer

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The majority of hypoxic cells in squamous cell carcinomas of the head and neck and cervix express involucrin, a molecular marker for differentiation. This raises the question of whether involucrin is an oxygen-regulated protein and, if so, whether it could serve as an endogenous marker for tumour hypoxia. Consistent with oxygen regulation, involucrin protein was found to increase with increasing hypoxia in confluent cultures of moderately differentiated human SCC9 cells. Cells harvested at the point of confluence and exposed to graded concentrations of oxygen revealed a K m of approximately 15 mmHg for involucrin induction. This is similar to K m s for HIF1a, CAIX and VEGF. Involucrin induction showed a steep dependence on pO 2 with a transition from minimum to maximum expression occurring over less than an order of magnitude change in pO 2 . In contrast to SCC9 cells, involucrin was not induced by hypoxia in poorly differentiated SCC4 cells. It is concluded that involucrin is an oxygen-regulated protein, but that differentiation modulates its transcription status with respect to hypoxia induction.

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The human involucrin gene contains spatially distinct regulatory elements that regulate expression during early versus late epidermal differentiation

Cited by 41 publications

References 44 publications

Reduced expression of ΔΝp63α in cervical squamous cell carcinoma

Reduced expression of ΔΝp63α in cervical squamous cell carcinoma

Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas

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