Signal transduction by the JNK group of MAP kinases.

Werner, Sabine, and Richard Grose. Regulation of Wound Healing by Growth Factors and Cytokines. Physiol Rev 83: 835–870, 2003; 10.1152/physrev.00032.2002.—Cutaneous wound healing is a complex proce...

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Regulation of Wound Healing by Growth Factors and Cytokines

There has been much effort recently to probe the long-recognized relationship between the pathological processes of infection, inflammation and cancer. For example, epidemiological studies have shown that approximately 15% of human deaths from cancer are associated with chronic viral or bacterial infections. This Review focuses on the molecular mechanisms that connect infection, inflammation and cancer, and it puts forward the hypothesis that activation of nuclear factor-kappaB (NF-kappaB) by the classical, IKK-beta (inhibitor-of-NF-kappaB kinase-beta)-dependent pathway is a crucial mediator of inflammation-induced tumour growth and progression, as well as an important modulator of tumour surveillance and rejection.

NF-kappaB: linking inflammation and immunity to cancer development and progression.

The transcription factor AP-1 (activator protein-1) is involved in cellular proliferation, transformation and death. Using mice and cells lacking AP-1 components, the target-genes and molecular mechanisms mediating these processes were recently identified. Interestingly, the growth-promoting activity of c-Jun is mediated by repression of tumour suppressors, as well as upregulation of positive cell cycle regulators. Mostly, c-Jun is a positive regulator of cell proliferation, whereas JunB has the converse effect. The intricate relationships between the different Jun proteins, their activities and the mechanisms that mediate them will be discussed.

AP-1 as a regulator of cell life and death

Cancer can be perceived as a disease of communication between and within cells. The aberrations are pleiotropic, but mitogen-activated protein kinase (MAPK) pathways feature prominently. Here, we discuss recent findings and hypotheses on the role of MAPK pathways in cancer. Cancerous mutations in MAPK pathways are frequently mostly affecting Ras and B-Raf in the extracellular signal-regulated kinase pathway. Stress-activated pathways, such as Jun N-terminal kinase and p38, largely seem to counteract malignant transformation. The balance and integration between these signals may widely vary in different tumours, but are important for the outcome and the sensitivity to drug therapy.

MAP kinase signalling pathways in cancer.

The c-jun proto-oncogene encodes a component of the mitogen-inducible immediate-early transcription factor AP-1 and has been implicated as a positive regulator of cell proliferation and G1-to-S-phase progression. Here we report that fibroblasts derived from c-jun-/- mouse fetuses exhibit a severe proliferation defect and undergo a prolonged crisis before spontaneous immortalization. The cyclin D1- and cyclin E-dependent kinases (CDKs) and transcription factor E2F are poorly activated, resulting in inefficient G1-to-S-phase progression. Furthermore, the absence of c-Jun results in elevated expression of the tumor suppressor gene p53 and its target gene, the CDK inhibitor p21, whereas overexpression of c-Jun represses p53 and p21 expression and accelerates cell proliferation. Surprisingly, protein stabilization, the common mechanism of p53 regulation, is not involved in up-regulation of p53 in c-jun-/- fibroblasts. Rather, c-Jun regulates transcription of p53 negatively by direct binding to a variant AP-1 site in the p53 promoter. Importantly, deletion of p53 abrogates all defects of cells lacking c-Jun in cell cycle progression, proliferation, immortalization, and activation of G1 CDKs and E2F. These results demonstrate that an essential, rate-limiting function of c-Jun in fibroblast proliferation is negative regulation of p53 expression, and establish a mechanistic link between c-Jun-dependent mitogenic signaling and cell-cycle regulation.

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Control of cell cycle progression by c-Jun is p53 dependent

c-Jun and JunB Antagonistically Control Cytokine-Regulated Mesenchymal–Epidermal Interaction in Skin

Organotypic Cocultures with Genetically Modified Mouse Fibroblasts as a Tool to Dissect Molecular Mechanisms Regulating Keratinocyte Growth and Differentiation

The invention relates to genetically modified fibroblast cells which comprise the following properties: (a) a gene, encoding a subunit of the transcription factor AP-1, of its genome is inactivated and/or a component, acting on the AP-1 transcription factor of the signal transduction pathway is modified resulting in a modified AP-1 activity; (b) functionally linked with a promoter, it contains in an expression vector the gene from (a) in a form such that the active subunit is only expressed after induction of the promoter or the subunit encoded by the gene is present in inactive form and a form that can be activated. Furthermore, the invention relates to a method which uses the fibroblast cell according to the invention to identify a compound which can support, inhibit or modify the AP-1-dependent differentiation and/or proliferation of keratinocytes or a gene which is involved in the AP-1-dependent differentiation and/or proliferation of keratinocytes as well as to the use of the test compound identified according to the method of the invention and the gene for treating or diagnosing diseases associated with a disturbed proliferation and/or differentiation of keratinocytes.

Andrea Kolbus

Papers

Control of cell cycle progression by c-Jun is p53 dependent

c-Jun and JunB Antagonistically Control Cytokine-Regulated Mesenchymal–Epidermal Interaction in Skin

Organotypic Cocultures with Genetically Modified Mouse Fibroblasts as a Tool to Dissect Molecular Mechanisms Regulating Keratinocyte Growth and Differentiation

Genetically modified fibroblast cells