Sequential Changes in Gene Expression during Epidermal Differentiation

Roop, Dennis R.; Nakazawa, Hisayoshi; Mehrel, Thomas; Cheng, Christina; Chung, Su Yun; Rothnagel, Joseph A.; Steinert, Peter M.; Yuspa, Stuart H.

doi:10.1007/978-94-011-9702-1_21

Cited by 15 publications

(17 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…K14 immunoreactivity within MycER TAM -induced epidermal hyperplasias was pronounced in the basal and immediately adjacent suprabasal layers, decreasing in intensity through to the granular layer -an essentially reciprocal distribution to that of involucrin (Figure 1c and d). K14 protein, however, has been shown to persist into the suprabasal compartment of hyperplastic epidermis despite the downregulation of K14 mRNA upon commitment to differentiation (Roop et al, 1988;Stoler et al, 1988;Waikel et al, 1999). We therefore determined the expression of an alternative marker of basal keratinocytes, p63 protein, recently demonstrated to be more closely associated with the proliferative potential of keratinocytes and lost upon the transition from basal to suprabasal compartment (Parsa et al, 1999;Liefer et al, 2000;Pellegrini et al, 2001;Koster et al, 2004).…”

Section: Keratinocyte Differentiation Overwhelms Myc-driven Proliferamentioning

confidence: 98%

Defining the temporal requirements for Myc in the progression and maintenance of skin neoplasia

et al. 2004

View full text Add to dashboard Cite

The homeostatic integrity of skin epidermis is maintained by a balance between keratinocyte proliferation, on one hand, and terminal differentiation combined with outward migration and shedding, on the other. Perturbation of this balance in favor of proliferation can result in hyperplasia and, potentially, tumorigenesis. We have previously described a reversible transgenic mouse model of epidermal neoplasia in which expression of an acutely regulatable form of Myc, MycER TAM , is targeted to epidermis via the involucrin promoter. In this model, sustained activation of MycER TAM induces a complex neoplastic lesion involving marked hyperplasia of lessdifferentiated suprabasal cells, angiogenesis and overt papillomatosis. Subsequent deactivation of MycER TAM triggers complete papilloma regression. Here, we provide evidence that Myc-induced papillomas are self-limiting because of the eventual differentiation of MycER TAMexpressing keratinocytes. Thus, keratinocyte differentiation eventually prevails over Myc-induced proliferation. We also show that regression of Myc-induced papillomas following MycER TAM deactivation occurs through a combination of growth arrest and irreversible differentiation. Finally, we demonstrate that transient deactivation of Myc is sufficient to expel keratinocytes irreversibly from the proliferative compartment and render them refractory to the mitogenic influence of subsequent Myc reactivation. Such observations illustrate the potential utility of even short-term inhibition of oncogenic lesions in the treatment of cancer.

show abstract

Section: Keratinocyte Differentiation Overwhelms Myc-driven Proliferamentioning

confidence: 98%

Defining the temporal requirements for Myc in the progression and maintenance of skin neoplasia

et al. 2004

View full text Add to dashboard Cite

show abstract

“…K1, K14, K6 and K13 expression was analysed using monospeci®c antibodies developed by Roop et al (1984). Sections were incubated with the antibodies at a 1 : 500 dilution for K1, K14 and K6 and 1 : 800 for K13, followed by a secondary biotin-labeled anti-rabbit IgG and the avidin-peroxidase complex (ABC Vectastain, Elite, Vector Lab).…”

Section: Immunohistochemical Staining For Keratinsmentioning

confidence: 99%

Overexpression of insulin-like growth factor-1 induces hyperplasia, dermal abnormalities, and spontaneous tumor formation in transgenic mice

et al. 1997

View full text Add to dashboard Cite

Transgenic animals were developed to assess the role of insulin-like growth factor 1 (IGF-1) in skin growth, di erentiation and organization, as well as its importance in tumor formation. Expression of a human IGF-1 cDNA was targeted to the interfollicular epidermis of transgenic mice using a human keratin 1 promoter construct (HK1). Transgenic animals (HK1.IGF-1 mice) could be identi®ed at birth by early ear unfolding and excessive ear and skin growth compared to nontransgenic littermates. Further examination of the skin from these mice showed epidermal hyperplasia and hyperkeratosis, marked thickening of the dermis and hypodermis, and early hair follicle generation in newborns. The severity of this phenotype correlated with transgene expression both of which subsided with age. Adult HK1.IGF-1 mice developed spontaneous tumors following treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) alone and exhibited an exaggerated epidermal proliferative response following treatment with the tumor promoter compared to non transgenic littermates. Additionally, HK1.IGF-1 transgenic mice developed papillomas faster and in markedly greater numbers compared to non-transgenic littermates in standard initiation-promotion experiments. The data presented suggest an important role for IGF-1 in the process of multistage carcinogenesis in mouse skin.

show abstract

“…In mouse and human skin, the proliferative basal layer consists of cells expressing transcripts encoding keratins 5 and 14. As keratinocytes withdraw from the cell cycle, they undergo spinous di erentiation, characterized by the downregulation of keratins 5 and 14, and the induction of transcripts encoding keratins 1 and 10 (K1 and K10) (Roop et al, 1988;Stoler et al, 1988;Fuchs, 1990). Transcripts encoding K1 and K10 are subsequently down-regulated in the granular layer, where the late marker genes loricrin and ®laggrin are induced (Roop et al, 1988;Fuchs, 1990).…”

Section: Introductionmentioning

confidence: 99%

“…As keratinocytes withdraw from the cell cycle, they undergo spinous di erentiation, characterized by the downregulation of keratins 5 and 14, and the induction of transcripts encoding keratins 1 and 10 (K1 and K10) (Roop et al, 1988;Stoler et al, 1988;Fuchs, 1990). Transcripts encoding K1 and K10 are subsequently down-regulated in the granular layer, where the late marker genes loricrin and ®laggrin are induced (Roop et al, 1988;Fuchs, 1990). In addition, keratinocyte transglutaminases are activated in the granular layer to catalyze the formation of corni®ed envelopes (reviewed in Polakowska and Goldsmith, 1991), insoluble structures composed of precursor proteins involucrin (Rice and Green, 1979), small proline rich (spr) proteins (Kartasova et al, 1987;Marvin et al, 1992), loricrin (Mehrel et al, 1990), and other components (Steinert and Merekov, 1995).…”

Section: Introductionmentioning

confidence: 99%

Opposing activities of c-Fos and Fra-2 on AP-1 regulated transcriptional activity in mouse keratinocytes induced to differentiate by calcium and phorbol esters

Rutberg

Sáez

et al. 1997

Oncogene

View full text Add to dashboard Cite

The major di erentiation products of maturing keratinocytes contain AP-1 regulatory motifs, and AP-1 DNA binding activity increases in cultured keratinocytes induced to di erentiate by calcium. Here, we have analysed AP-1 transcriptional activity in mouse keratinocytes treated with calcium and 12-O-tetradecanoyl phorbol-13-acetate (TPA), two agents that induce terminal di erentiation of keratinocytes with di erent phenotypic consequences. Reporter constructs representing multimers of AP-1 sequences found in keratinocyte marker genes demonstrated that the calcium-induced AP-1 DNA binding activity does not correlate with transcriptional activation. Moreover, expression from active subunits of the pro®laggrin and spr 1 promoters increased in calcium-treated keratinocytes when the AP-1 sites were disrupted, indicating that AP-1 may negatively regulate certain promoters in these cells. In contrast, AP-1 reporter activity was increased in keratinocytes treated with TPA. This induction was dependent upon the expression of c-Fos since AP-1 transcriptional activity was not increased in TPA-treated keratinocytes derived from c-fos null mice. Analysis of AP-1 protein expression in calcium-and TPA-treated keratinocytes demonstrated that only TPA increased the expression of c-Jun, while Jun B and Jun D were induced by both of these agents. c-Fos was expressed only in TPA treated keratinocytes, Fra-2 was expressed only in calcium-treated cells, and Fra-1 was expressed in both. Exogenous expression of Fra-2 repressed AP-1 transcriptional activity in TPA-treated keratinocytes, while c-Fos expression activated the AP-1 sequence in calcium-treated keratinocytes. These data indicate that Fra-2 and c-Fos play opposing roles in regulating AP-1 activity in keratinocytes and that multiple inducerdependent regulatory pathways may exist for the expression of keratinocyte di erentiation markers.

show abstract

Sequential Changes in Gene Expression during Epidermal Differentiation

Cited by 15 publications

References 31 publications

Defining the temporal requirements for Myc in the progression and maintenance of skin neoplasia

Defining the temporal requirements for Myc in the progression and maintenance of skin neoplasia

Overexpression of insulin-like growth factor-1 induces hyperplasia, dermal abnormalities, and spontaneous tumor formation in transgenic mice

Opposing activities of c-Fos and Fra-2 on AP-1 regulated transcriptional activity in mouse keratinocytes induced to differentiate by calcium and phorbol esters

Contact Info

Product

Resources

About