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ARNT controls the expression of epidermal differentiation genes through HDAC- and EGFR-dependent pathways

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ARNT controls the expression of epidermal differentiation genes through HDAC- and EGFR-dependent pathways. / Robertson, E. Douglas; Weir, Lynda; Romanowska, Malgorzata; Leigh, Irene M.; Panteleyev, Andrey A. (Lead / Corresponding author).

In: Journal of Cell Science, Vol. 125, No. 14, 15.07.2012, p. 3320-3332.

Research output: Contribution to journalArticle

Harvard

Robertson, ED, Weir, L, Romanowska, M, Leigh, IM & Panteleyev, AA 2012, 'ARNT controls the expression of epidermal differentiation genes through HDAC- and EGFR-dependent pathways' Journal of Cell Science, vol 125, no. 14, pp. 3320-3332.

APA

Robertson, E. D., Weir, L., Romanowska, M., Leigh, I. M., & Panteleyev, A. A. (2012). ARNT controls the expression of epidermal differentiation genes through HDAC- and EGFR-dependent pathways. Journal of Cell Science, 125(14), 3320-3332doi: 10.1242/jcs.095125

Vancouver

Robertson ED, Weir L, Romanowska M, Leigh IM, Panteleyev AA. ARNT controls the expression of epidermal differentiation genes through HDAC- and EGFR-dependent pathways. Journal of Cell Science. 2012 Jul 15;125(14):3320-3332.

Author

Robertson, E. Douglas; Weir, Lynda; Romanowska, Malgorzata; Leigh, Irene M.; Panteleyev, Andrey A. (Lead / Corresponding author) / ARNT controls the expression of epidermal differentiation genes through HDAC- and EGFR-dependent pathways.

In: Journal of Cell Science, Vol. 125, No. 14, 15.07.2012, p. 3320-3332.

Research output: Contribution to journalArticle

Bibtex - Download

@article{fa6f369d60354725983d0049c86ade13,
title = "ARNT controls the expression of epidermal differentiation genes through HDAC- and EGFR-dependent pathways",
author = "Robertson, {E. Douglas} and Lynda Weir and Malgorzata Romanowska and Leigh, {Irene M.} and Panteleyev, {Andrey A.}",
year = "2012",
volume = "125",
number = "14",
pages = "3320--3332",
journal = "Journal of Cell Science",
issn = "0021-9533",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - ARNT controls the expression of epidermal differentiation genes through HDAC- and EGFR-dependent pathways

A1 - Robertson,E. Douglas

A1 - Weir,Lynda

A1 - Romanowska,Malgorzata

A1 - Leigh,Irene M.

A1 - Panteleyev,Andrey A.

AU - Robertson,E. Douglas

AU - Weir,Lynda

AU - Romanowska,Malgorzata

AU - Leigh,Irene M.

AU - Panteleyev,Andrey A.

PY - 2012/7/15

Y1 - 2012/7/15

N2 - <p>Previously we showed that spatial and developmental modulation of ARNT (HIF1 beta) expression in mouse epidermis is essential for maintenance of keratinocyte differentiation, proper formation of the barrier and normal desquamation. Here, using lentiviral suppression or induction of ARNT in TERT-immortalized (N-TERT) and HaCaT cells we assessed the nature and mechanisms of ARNT involvement in control of differentiation in human epidermal keratinocytes. ARNT depletion did not affect the levels of basal keratins K5 and K14, but significantly induced expression of several key differentiation markers (an effect abolished by EGF supplementation). Furthermore, ARNT deficiency resulted in the downregulation of amphiregulin (AREG) the most highly expressed EGFR ligand in human keratinocytes - whereas upregulation of ARNT showed the opposite. In ARNT-deficient monolayer cultures and 3D epidermal equivalents, the downregulation of AREG was concurrent with a decline of EGFR and ERK1/2 phosphorylation. TSA, a potent suppressor of HDAC activity, abolished the effects of ARNT deficiency, implying a role for HDACs in ARNT-dependent modulation of the AREG-EGFR pathway and downstream epidermal genes. Total HDAC activity was significantly increased in ARNT-depleted cells and decreased with ARNT overexpression. ARNT-dependent shifts in HDAC activity were specifically attributed to significant changes in the levels of HDAC1, HDAC2 and HDAC3 proteins (but not mRNA) in both monolayer and 3D cultures. Collectively, our results suggest that ARNT controls AREG expression and the downstream EGFR-ERK pathway in keratinocytes, at least in part, by modulating HDAC activity. This novel regulatory pathway targeting advanced stages of epidermal differentiation might have important implications for skin pathology such as psoriasis, atopic dermatitis and cancer.</p>

AB - <p>Previously we showed that spatial and developmental modulation of ARNT (HIF1 beta) expression in mouse epidermis is essential for maintenance of keratinocyte differentiation, proper formation of the barrier and normal desquamation. Here, using lentiviral suppression or induction of ARNT in TERT-immortalized (N-TERT) and HaCaT cells we assessed the nature and mechanisms of ARNT involvement in control of differentiation in human epidermal keratinocytes. ARNT depletion did not affect the levels of basal keratins K5 and K14, but significantly induced expression of several key differentiation markers (an effect abolished by EGF supplementation). Furthermore, ARNT deficiency resulted in the downregulation of amphiregulin (AREG) the most highly expressed EGFR ligand in human keratinocytes - whereas upregulation of ARNT showed the opposite. In ARNT-deficient monolayer cultures and 3D epidermal equivalents, the downregulation of AREG was concurrent with a decline of EGFR and ERK1/2 phosphorylation. TSA, a potent suppressor of HDAC activity, abolished the effects of ARNT deficiency, implying a role for HDACs in ARNT-dependent modulation of the AREG-EGFR pathway and downstream epidermal genes. Total HDAC activity was significantly increased in ARNT-depleted cells and decreased with ARNT overexpression. ARNT-dependent shifts in HDAC activity were specifically attributed to significant changes in the levels of HDAC1, HDAC2 and HDAC3 proteins (but not mRNA) in both monolayer and 3D cultures. Collectively, our results suggest that ARNT controls AREG expression and the downstream EGFR-ERK pathway in keratinocytes, at least in part, by modulating HDAC activity. This novel regulatory pathway targeting advanced stages of epidermal differentiation might have important implications for skin pathology such as psoriasis, atopic dermatitis and cancer.</p>

U2 - 10.1242/jcs.095125

DO - 10.1242/jcs.095125

M1 - Article

JO - Journal of Cell Science

JF - Journal of Cell Science

SN - 0021-9533

IS - 14

VL - 125

SP - 3320

EP - 3332

ER -

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