Epidermal growth factor and transforming growth factor alpha specifically induce the activation- and hyperproliferation-associated keratins 6 and 16.

Jiang, C K; Magnaldo, Thierry; Ohtsuki, Mamitaro; Freedberg, Irwin M.; Bernerd, Françoise; Blumenberg, Miroslav

doi:10.1073/pnas.90.14.6786

Cited by 174 publications

(133 citation statements)

References 30 publications

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“…9B (60)), which means that AP1 transcription factors play no role in the signaling by TNF␣. Parenthetically, the responsiveness to EGF parallels the responsiveness to AP1, suggesting that AP1 transcription factors convey the EGF signal (18). Thus, the TNF␣-and the EGF-responsive elements in the K6b promoter DNA are distinct and independent.…”

Section: Tnf␣ Activates the K6b Promoter Through Nfb And C/ebp␤ Transmentioning

confidence: 94%

“…DNA Constructs-The plasmids containing keratin promoters and the control plasmids pRSVZ have been described previously (17,18,60). The plasmids containing the IL-8 promoter and (NFB)3-CAT were gifts from J. Vilcek (52); and those expressing NFB proteins were from A. Beg and D. Baltimore (35); those expressing C/EBP␤ were from S. Chen-Kiang (61); IB and His-NFB were from S. Ghosh (62,63), and CHOP was from D. Ron (64).…”

Section: Methodsmentioning

confidence: 99%

“…Our previous results have demonstrated that EGF or TGF␣, the proliferative signals, induce the expression of keratins K6b and K16 (17,18). Therefore, focusing on the K6b keratin, we decided to determine whether TNF␣, which is a strong proinflammatory but not a proliferative signal in keratinocytes (19), affects its expression.…”

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confidence: 99%

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Inflammatory Versus Proliferative Processes in Epidermis

Komine¹,

Rao²,

Kaneko³

et al. 2000

Journal of Biological Chemistry

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Epidermal keratinocytes respond to injury by becoming activated, i.e. hyperproliferative, migratory, and proinflammatory. These processes are regulated by growth factors and cytokines. One of the markers of activated keratinocytes is keratin K6. We used a novel organ culture system to show that tumor necrosis factor ␣ (TNF␣) induces the expression of K6 protein and mRNA in human skin. Multiple isoforms of K6 are encoded by distinct genes and have distinct patterns of expression. By having shown previously that proliferative signals, such as epidermal growth factor (EGF), induce expression of the cytoskeletal protein keratin K6b, we here demonstrate that the same isoform, K6b, is also induced by TNF␣, a proinflammatory cytokine. Specifically, TNF␣ induces the transcription of the K6b gene promoter. By using co-transfection, specific inhibitors, and antisense oligonucleotides, we have identified NFB and C/EBP␤ as the transcription factors that convey the TNF␣ signal. Both transcription factors are necessary for the induction of K6b by TNF␣ and act as a complex, although only C/EBP␤ binds the K6b promoter DNA. By using transfection, site-directed mutagenesis, and footprinting, we have mapped the site that responds to TNF␣, NFB, and C/EBP␤. This site is separate from the one responsive to EGF and AP1. Our results show that the proinflammatory (TNF␣) and the proliferative (EGF) signals in epidermis separately and independently regulate the expression of the same K6b keratin isoform. Thus, the cytoskeletal responses in epidermal cells can be precisely tuned by separate proliferative and inflammatory signals to fit the nature of the injuries that caused them.

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Section: Tnf␣ Activates the K6b Promoter Through Nfb And C/ebp␤ Transmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

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Inflammatory Versus Proliferative Processes in Epidermis

Komine¹,

Rao²,

Kaneko³

et al. 2000

Journal of Biological Chemistry

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“…With the accumulation of K6, K16, and K17, the protein levels of K1 and K10 are decreased (Mansbridge and Knapp, 1987;Paladini et al, 1996). First insights into the regulation of the K6 induction in wound healing came from in vitro studies with the use of human skin keratinocytes, which revealed AP-1 and epidermal growth factor-responsive elements in the human and bovine K6 promoter region (Jiang et al, 1993;Navarro et al, 1995). Epidermal growth factor receptor signaling was found to be rapidly induced after injury (Martin and Nobes, 1992;Martin, 1997).…”

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confidence: 99%

Complete Cytolysis and Neonatal Lethality in Keratin 5 Knockout Mice Reveal Its Fundamental Role in Skin Integrity and in Epidermolysis Bullosa Simplex

Peters

Kirfel

Büssow³

et al. 2001

MBoC

110

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In human patients, a wide range of mutations in keratin (K) 5 or K14 lead to the blistering skin disorder epidermolysis bullosa simplex. Given that K14 deficiency does not lead to the ablation of a basal cell cytoskeleton because of a compensatory role of K15, we have investigated the requirement for the keratin cytoskeleton in basal cells by inactivating the K5 gene in mice. We report that the K5 Ϫ/Ϫ mice die shortly after birth, lack keratin filaments in the basal epidermis, and are more severely affected than K14 Ϫ/Ϫ mice. In contrast to the K14 Ϫ/Ϫ mice, we detected a strong induction of the wound-healing keratin K6 in the suprabasal epidermis of cytolyzed areas of postnatal K5 Ϫ/Ϫ mice. In addition, K5 and K14 mice differed with respect to tongue lesions. Moreover, we show that in the absence of K5 and other type II keratins, residual K14 and K15 aggregated along hemidesmosomes, demonstrating that individual keratins without a partner are stable in vivo. Our data indicate that K5 may be the natural partner of K15 and K17. We suggest that K5 null mutations may be lethal in human epidermolysis bullosa simplex patients. INTRODUCTIONKeratin (K) intermediate filaments (IFs) belong to a gene family that is organized into two subfamilies, coding for type I (K9 -20) and type II keratins (K1-8). At least one member of each family is necessary to form heterodimeric IFs. In epidermis, keratins display a complex expression pattern that is widely assumed to reflect the structural requirements of distinct epidermal compartments (Fuchs and Cleveland, 1998).The major keratins in the basal layer of stratified epithelia are K5, K14, and K15 (Fuchs and Green, 1978, 1980;Moll et al., 1982;Leube et al., 1988;Lloyd et al., 1995). In wound healing or in hyperproliferative disorders, the keratin pair K6 and K16 is transiently expressed in the suprabasal layers instead of K1, K2e, and K10 (for review, see McGowan and Coulombe, 1998). The functional significance of the highly patterned expression profile of keratins is still poorly understood, but evidence is accumulating that they have distinct functions in epidermis (Paladini and Coulombe, 1999).The structural function of keratins was elucidated by the discovery of point mutations in human epidermal keratin genes (Corden and McLean, 1996), preceded by studies on transgenic mice expressing mutant keratin subunits . These mutations cause a number of inherited human skin disorders such as epidermolysis bullosa simplex (EBS) (Bonifas et al., 1991;Coulombe et al., 1991;Lane et al., 1992;Rothnagel et al., 1995;Corden and McLean, 1996). The characteristic feature of EBS is epidermal blistering resulting from cytolysis of basal keratinocytes. On the basis of these observations, it was suggested that the overall function of epidermal keratins was to provide the reinforcement of the epidermis and the maintenance of cellular integrity under mechanical and thermal stress. Several mice carrying null or dominant keratin mutations that affect epidermal integrity have added further support to t...

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“…Diversos autores já observaram a presença de grandes quantidades de TGF-∝ nas células do colesteatoma. O TGF-∝ é uma citocina que aumenta a transcrição do gene da citoqueratina 16, ativando a proliferação dos queratinócitos 10 . Além do TGF-∝, várias outras citocinas têm sido demonstradas em grandes quantidades no colesteatoma da orelha média, quando comparado à epiderme do meato acústico externo.…”

Section: Quanto àS Características Histológicas E Imunohistoquímicas unclassified

Estudo comparativo de aspectos histológicos e imunohistoquímicos entre o colesteatoma espontâneo do meato acústico externo e o colesteatoma adquirido da orelha média

Ribeiro¹,

Pereira²,

Almeida³

2004

Rev. Bras. Otorrinolaringol.

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Comparative study of the histological and immunohisochemical aspects of the spontaneous cholesteatomas of the external ear canal and the acquired cholesteatoma of the middle ear Resumo / SummaryObj etivo: Neste trabalho foram avaliadas as características histológicas e imunohistoquímicas (Ki-67 e CK-16) do colesteatoma espontâneo do meato acústico externo comparando-as com as do colesteatoma adquirido da orelha média. Forma de estudo: Caso controle. Material e Método: Fragmentos de colesteatoma do meato acústico externo foram submetidos a estudo histológico e imunohistoquímico com o intuito de verificar a expressão da CK16 e do antígeno nuclear Ki-67 nas células de sua matriz, e os resultados foram comparados com os encontrados no colesteatoma adquirido da orelha média. Resultados: Os aspectos histológico e imunohistoquímico quanto à presença da CK16 e do antígeno nuclear Ki-67 na matriz do colesteatoma do meato acústico externo foram idênticos àqueles encontrados no colesteatoma adquirido da orelha média. Discussão: Acreditamos que a ocorrência do colesteatoma do meato acústico externo seja devido ao comportamento anormal de células com potencial hiperproliferativo no epitélio do meato. Este potencial estaria relacionado com a presença da CK16 em uma região onde estes marcadores não são usualmente encontrados. Esta característica hiperproliferativa do colesteatoma do meato fica patente pela presença do antígeno nuclear Ki-67 nas células suprabasais de sua epiderme. Possivelmente esta doença deve ser desencadeada pela interação desta citoqueratina (CK16) com citocinas presentes no tecido conjuntivo subepitelial inflamado, como a TGF-∝. Conclusão: As características histológicas (presença de cones epiteliais) e histoquímicas (expressão da CK16 e do antígeno nuclear KI-67) são idênticas no colesteatoma adquirido da orelha média e no colesteatoma espontâneo do meato acústico externo. Histological and immunohistochemical aspects studied were identical in both types of cholesteatomas studied. Discussion: This study suggests that cholesteatomas of the external ear canal are caused by na abnormal behavior of the cells of the epithelium of the external canal with hyperproliferative properties. This potential could be explained by the presence of CK-16 at a location where these markers are not usually found. The hyperproliferative characteristic of the external ear canal cholesteatoma is possible due to the presence of the K-67 nuclear antigen in the epidermal suprabasal cells. It is possible that the disease is caused by an interaction between CK-16 and the cytocines (TGF-alpha),which are present in the subepithelial connective tissue undergoing na inflammatory process. Conclusions: The histological (presence of epithelial cones) and immunohistochemical (expression of CK 16 and the nuclear antigen KI-67) characteristics of both the external ear canal and the acquired middle ear cholesteatomas are identical. Fernando dePalavras-chave: colesteatoma, meato acústico externo, orelha média, CK16, KI-67.

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Epidermal growth factor and transforming growth factor alpha specifically induce the activation- and hyperproliferation-associated keratins 6 and 16.

Cited by 174 publications

References 30 publications

Inflammatory Versus Proliferative Processes in Epidermis

Inflammatory Versus Proliferative Processes in Epidermis

Complete Cytolysis and Neonatal Lethality in Keratin 5 Knockout Mice Reveal Its Fundamental Role in Skin Integrity and in Epidermolysis Bullosa Simplex

Estudo comparativo de aspectos histológicos e imunohistoquímicos entre o colesteatoma espontâneo do meato acústico externo e o colesteatoma adquirido da orelha média

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