Function and regulation of AP-1 subunits in skin physiology and pathology

Angel, Peter; Szabowski, Axel; Schorpp-Kistner, Marina

doi:10.1038/sj.onc.1204380

Cited by 376 publications

(375 citation statements)

References 116 publications

(103 reference statements)

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“…Investigation of the molecular mechanism of carcinoma cell differentiation/ dedifferentiation is a momentous subject in cancer cell biology and may contribute to the development of a novel strategy to relieve patient suffering from the disease. Although investigators reported that various factors are involved in carcinoma cell differentiation and dedifferentiation, accumulating evidence implies that transcriptional misregulation takes a critical part in the events (Angel et al, 1996;Hunter, 1997;Visvader et al, 1997;Battle et al, 2000;Cano et al, 2000). In the present study, our data demonstrate for the first time that LMO4 and LDB1 form protein complexes in the nucleus and are expressed in carcinoma cells at the invasive front, and their immunoreactivity is increased in lessdifferentiated carcinomas and in metastasised lymph nodes.…”

Section: Discussionsupporting

confidence: 59%

The LIM-only protein, LMO4, and the LIM domain-binding protein, LDB1, expression in squamous cell carcinomas of the oral cavity

et al. 2003

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Carcinoma cells can lose their epithelial cell characteristics and dedifferentiate into a fibroblast-like cell during progression of a neoplasm. Aberrant expression of oligomeric transcriptional complexes contributes to progression of carcinomas. Although individual transcription factors initiating progression remain unknown, LIM-only protein (LMO) and LIM-domain binding protein (LDB) negatively regulate breast carcinoma cell differentiation. In this study, we investigated the expression of LMO4 and LDB in squamous cell carcinomas of the oral cavity. LMO4 mRNA was amplified in four of six carcinoma tissues and eight of 12 carcinoma cell lines, and LDB1 in three carcinoma tissues and 11 cell lines examined. Immunoprecipitation studies revealed that LMO4 and LDB1 interact with each other in the nuclear milieu of the carcinoma cells indicating the presence of an LMO4-LDB1-mediated transcription complex. Both LMO4 and LDB1 proteins were preferentially localised in the nuclei of carcinoma cells at the invasive front and the immunoreactivity was increased in less-differentiated carcinoma tissues (Po0.01). Carcinoma cells metastasised to the cervical lymph nodes with increased immunoreactivity compared to the primary site of neoplasm (Po0.05). These data suggest that the LMO4 -LDB1 complexes may be involved in carcinoma progression possibly through dedifferentiation of squamous carcinoma cells of the oral cavity.

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Section: Discussionsupporting

confidence: 59%

The LIM-only protein, LMO4, and the LIM domain-binding protein, LDB1, expression in squamous cell carcinomas of the oral cavity

et al. 2003

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“…AP-1 target genes are differentially regulated by distinct AP-1 dimers. The dynamic changes in Jun and Fos composition after stress-stimuli balance discrete signals that play a key role in defining whether cells undergo apoptosis, survival or senescence (4). Many compounds can induce apoptosis in tumor cells by interfering with AP-1.…”

Section: Introductionmentioning

confidence: 99%

During Human Melanoma Progression AP‐1 Binding Pairs are Altered with Loss of c‐Jun In Vitro

Yang

McNulty

Meyskens

2004

Pigment Cell Research

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We demonstrated previously that c‐Jun, JunB and c‐Fos RNA were dysregulated in metastatic melanoma cells compared with normal human melanocytes. The purpose of this study was to evaluate the distribution in composition of AP‐1 dimers in human melanoma pathogenesis. We investigated AP‐1 dimer pairing in radial growth phase‐like (RGP) (w3211) and vertical growth phase‐like (VGP) (w1205) human melanoma cells and metastatic cell lines (cloned from patients, c83‐2c, c81‐46A, A375, respectively) compared with melanocytes using electrophoretic mobility shift assay (EMSA), Western blot and transfection analyses. There are progressive variations in AP‐1 composition in different melanoma cell lines compared with normal melanocytes, in which c‐Jun, JunD and FosB were involved in AP‐1 complexes. In w3211, c‐Jun, JunD and Fra‐1 were involved in AP‐1 binding, while in w1205, overall AP‐1 binding activity was decreased significantly and supershift binding was detected only with JunD antibodies. In metastatic c81‐46A and A375 cells, only JunD was involved in AP‐1 binding activity, but in a third (c83‐2c) c‐Jun, JunD and Fra‐1 were present. Western blot evaluation detected c‐Jun in melanocytes and w3211, but this component was decreased significantly or was not detectable in w1205, c81‐46A and A375 cells. In contrast, JunD protein was elevated in c81‐46A and c83‐2c cells compared with melanocytes and RGP and VGP cell lines. Normal melanocytes and c83‐2c cells (which have c‐Jun involved in AP‐1 binding), transfected with c‐Jun antisense and treated with cisplatin, showed higher viability compared with untransfected cells, while in c81‐46A cells (in which only JunD is detectable) no change in cell viability was observed following treatment with cisplatin and c‐jun antisense transfection. A dominant‐negative c‐Jun mutant (TAM67) significantly increased the soft agar colony formation of w3211 and c83‐2c cells. These results suggest that components of AP‐1, especially c‐Jun, may offer a new target for the prevention or treatment of human melanoma progression.

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“…21,22 Potentially, therefore, activated c-Jun could play an important role in stromal-epithelial interactions. 20,23 The Jun-family of proteins function as critical transcription factors, regulating the expression of many genes such as IGFs, fibroblast growth factors, epithelial growth factor, hepatocyte growth factor, and transforming growth factor-␤. It is not surprising then that they may also regulate downstream paracrine effectors between stromal and epithelial cells.…”

mentioning

confidence: 99%

Stromally Expressed c-Jun Regulates Proliferation of Prostate Epithelial Cells

Febbo

et al. 2007

The American Journal of Pathology

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Stromal-epithelial interactions play a critical role inBenign prostatic hyperplasia (BPH) is the most common age-related proliferative abnormality of the human prostate affecting elderly men throughout the world. Half of all men have BPH identifiable histologically by age 60, and by age 85 the prevalence is ϳ90%. 1 The excessive cell proliferation associated with BPH causes benign prostatic enlargement, bladder outlet obstruction, and lower urinary tract symptoms, which afflict the patients. 2 BPH is a histological diagnosis associated with both epithelial and stromal (fibroblasts and smooth muscle cells of prostate) hyperplasia. 3 Cellular alterations that include changes in proliferation, differentiation, apoptosis, and senescence in the epithelium and stroma are implicated in the pathogenesis of BPH. Medical treatments available to patients with BPH target both prostatic stromal and epithelial cells.Watchful waiting, pharmacological therapy, and surgery are three treatment modalities for BPH patients. Medical therapy is a long-term commitment for the patient. Surveys show that a large number of patients discontinue therapy, often because they perceive lack of efficacy and/or experience side effects. 4,5 We can accordingly improve our treatment of BPH by better targeted medical therapy to decrease the number of invasive therapies for this benign disease. Better alternative and improved therapies can be achieved by studying the normal and abnormal reciprocal cross talk between prostatic stromal and epithelial cells.Stromal-epithelial interactions play a critical role in the development and growth of the prostate gland and BPH. Cunha and colleagues 6 -8 have demonstrated that the stromal embryonic tissue is responsible for instructing the proper development of prostate epithelial cells. Tissue recombinants between embryonic urogenital sinus mesenchyme and adult prostatic tissue have demonstrated that the fetal mesenchyme can drive differentiation and growth of adult prostatic epithelial cells. 9 It has been proposed that BPH may be caused by reactivation of dormant embryonic growth in the adult stroma. 10 The proliferation of the stromal elements can stimulate the ingrowth of epithelial cells to produce a benign hyperplastic growth that is recognized

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Function and regulation of AP-1 subunits in skin physiology and pathology

Cited by 376 publications

References 116 publications

The LIM-only protein, LMO4, and the LIM domain-binding protein, LDB1, expression in squamous cell carcinomas of the oral cavity

The LIM-only protein, LMO4, and the LIM domain-binding protein, LDB1, expression in squamous cell carcinomas of the oral cavity

During Human Melanoma Progression AP‐1 Binding Pairs are Altered with Loss of c‐Jun In Vitro

Stromally Expressed c-Jun Regulates Proliferation of Prostate Epithelial Cells

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