The Proximal Promoter of the Mouse Loricrin Gene Contains a Functional AP-1 Element and Directs Keratinocyte-specific but Not Differentiation-specific Expression

DiSepio, Daniel; Jones, Alma H.; Longley, Mary A.; Bundman, Donnie S.; Rothnagel, Joseph A.; Roop, Dennis R.

doi:10.1074/jbc.270.18.10792

Cited by 89 publications

(88 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whether negative regulation is actually observed in vivo, however, is likely to re¯ect the dynamic array of AP-1 and CRE transcriptional regulators expressed in a cell at any given time. Keratinocyte marker genes that contain AP-1 DNA regulatory sequences include transglutaminase-1 (Yamada et al, 1994;Yamanishi et al, 1992), pro®laggrin (Presland et al, 1992;Jang et al, 1996), involucrin (Lopez-Bayghen et al, 1996;Takahashi and Iizuka 1993), keratin 1 (Hu et al, 1993;Lu et al, 1994;Zhang et al, 1994), keratin 5 (Casatorres et al, 1994), keratin 6 (Navarro et al, 1995;Bernerd et al, 1993) and keratin 18 (Oshima et al, 1990), loricin (DiSepio et al, 1995) and spr1 (Reddy et al, 1996); of these genes, the spr1 gene also contains a CRE sequence in a known regulatory position (Reddy et al, 1996). Thus, there is a wide range of keratinocyte genes with the potential for regulation by AP-1 and/or CRE binding proteins.…”

Section: Discussionmentioning

confidence: 99%

CRE DNA binding proteins bind to the AP-1 target sequence and suppress AP-1 transcriptional activity in mouse keratinocytes

et al. 1999

View full text Add to dashboard Cite

Previously, we have shown that nuclear extracts from cultured mouse keratinocytes induced to di erentiate by increasing the levels of extra-cellular calcium contain Fra-1, Fra-2, Jun B, Jun D and c-Jun proteins that bind to the AP-1 DNA binding sequence. Despite this DNA binding activity, AP-1 reporter activity was suppressed in these cells. Here, we have detected the CREB family proteins CREB and CREMa as additional participants in the AP-1 DNA binding complex in di erentiating keratinocytes. AP-1 and CRE DNA binding activity correlated with the induction of CREB, CREMa and ATF-1 and CREB phosphorylation at ser 133 (ser 133 phospho-CREB) in the transition from basal to di erentiating keratinocytes, but the activity of a CRE reporter remained unchanged. In contrast, the CRE reporter was activated in the presence of the dominantnegative (DN) CREB mutants, KCREB and A-CREB, proteins that dimerize with CREB family members and block their ability to bind to DNA. The increase in CRE reporter activity in the presence of these mutants suggests that CRE-mediated transcriptional activity is suppressed in keratinocytes through protein-protein interactions involving a factor that dimerizes with the CREB leucine zipper. In experiments where the A-CREB mutant was co-transfected with an AP-1 reporter construct, transcriptional activity was also increased indicating that a CREB family member binds AP-1 sites and represses AP-1 transcriptional activity as well. Exogenous expression of the transcriptional repressor CREMa down-regulated both CRE and AP-1 reporters in keratinocytes suggesting that this factor may contribute to the suppression of AP-1 transcriptional activity observed in di erentiating keratinocytes.

show abstract

Section: Discussionmentioning

confidence: 99%

CRE DNA binding proteins bind to the AP-1 target sequence and suppress AP-1 transcriptional activity in mouse keratinocytes

et al. 1999

View full text Add to dashboard Cite

show abstract

“…This is followed by the induction of squamous di erentiation-speci®c genes such as transglutaminase type 1 (TG I), keratin 10 and corni®n (Rieger and Franke, 1988;Marvin et al, 1992;Saunders et al, 1993b;Saunders and Jetten, 1994). Binding of transcription factors to the promoter regions of these genes has been demonstrated to activate or repress their activity (Leask et al, 1991;Casatorres et al, 1994;DiSepio et al, 1995;Welter et al, 1996;Medvedev et al, 1999). Thus, the regulation of epidermal gene expression is mediated by transcriptional events (Saunders et al, 1993a;Saunders and Jetten, 1994;Arany et al, 1997;Eckert et al, 1997) and results in the characteristic expression of genes required for di erent stages of squamous di erentiation.…”

Section: Introductionmentioning

confidence: 99%

E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes

et al. 2000

View full text Add to dashboard Cite

Squamous di erentiation of keratinocytes is associated with decreases in E2F-1 mRNA expression and E2F activity, and these processes are disrupted in squamous cell carcinoma cell lines. We now show that E2F-1 mRNA expression is increased in primary squamous cell carcinomas of the skin relative to normal epidermis. To explore the relationship between E2F-1 and squamous di erentiation further, we examined the e ect of altering E2F activity in primary human keratinocytes induced to di erentiate. Promoter activity for the proliferationassociated genes, cdc2 and keratin 14, are inhibited during squamous di erentiation. This inhibition can be inhibited by overexpression of E2F-1 in keratinocytes. Overexpression of E2F-1 also suppressed the expression of di erentiation markers (transglutaminase type 1 and keratin 10) in di erentiated keratinocytes. Blocking E2F activity by transfecting proliferating keratinocytes with dominant negative E2F-1 constructs inhibited the expression of cdc2 and E2F-1, but did not induce di erentiation. Furthermore, expression of the dominant negative construct in epithelial carcinoma cell lines and normal keratinocytes decreased expression from the cdc2 promoter. These data indicate that E2F-1 promotes keratinocyte proliferation-speci®c marker genes and suppresses squamous di erentiation-speci®c marker genes. Moreover, these data indicate that targeted disruption of E2F-1 activity may have therapeutic potential for the treatment of squamous carcinomas.

show abstract

“…AP-1 DNA binding sites have been shown to play an important role in cell-and tissue-speci®c expression of the loricrin (DiSepio et al, 1995), involucrin (Crish et al, 1993;Welter et al, 1995), keratin 5 (Casatorres et al, 1994) and keratin 1 (Rothnagel et al, 1993;Lu et al, 1994) genes in vitro and in vivo. Additional in vitro studies indicate that AP-1 proteins largely play a positive role in regulating the expression of keratinocyte genes that harbor AP-1 sites (Navarro et al, 1995;Yamada et al, 1994;Takahashi and Iizuka, 1993;DiSepio et al, 1995;Bernerd et al, 1993;Oshima et al, 1990), although in vivo studies will ultimately be required to provide a de®nitive demonstration of the role of AP-1 in regulating gene expression in the epidermis. Since epidermal genes containing AP-1 binding sites are both induced and suppressed during the di erentiation program, the possibility exists that the AP-1 transcription factor complex may contribute both positive and negative regulatory e ects during this process.…”

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

The Proximal Promoter of the Mouse Loricrin Gene Contains a Functional AP-1 Element and Directs Keratinocyte-specific but Not Differentiation-specific Expression

Cited by 89 publications

References 49 publications

CRE DNA binding proteins bind to the AP-1 target sequence and suppress AP-1 transcriptional activity in mouse keratinocytes

CRE DNA binding proteins bind to the AP-1 target sequence and suppress AP-1 transcriptional activity in mouse keratinocytes

E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes

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