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 G 1 -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 G 1 -to-S-phase progression. The control of mammalian cell proliferation by mitogens occurs largely during the G 1 phase of the cell cycle. During this period, extracellular signals are transduced by cytoplasmic signaling cascades to the nuclear cell cycle clock, where a decision is made between cell cycle progression and quiescence (Sherr 1994(Sherr , 1996. Among the earliest responses to mitogenic signaling is activation of transcription factors such as c-Jun, a subunit of activator protein 1 (AP-1) (Angel and Karin 1991). Transcriptional activation of yet-to-be-identified target genes by c-Jun and other immediate early transcription factors is thought to be essential for mitogen-induced progression through the cell cycle. A causal role of c-Jun in promoting cell division was indeed suggested by studies using microinjection of neutralizing antibodies or antisense RNA, which cause a partial G 0 arrest and block entry into S phase (Kovary and Bravo 1991;Riabowol et al. 1992;Smith and Prochownik 1992). Conversely, cell cycle distribution in cells overexpressing c-Jun is shifted toward S phase (Pfarr et al. 1994). c-Jun can act as an oncogene when mutated or expressed in a deregulated way, an ability that is shared by several cell cycle proteins promoting cell division such as cylin D1, cyclindependent kinase-4 (CDK4), c-Myc, and possibly E2F (Angel and Karin 1991; Sherr 1996;Weinberg 1996). In addition, c-Jun is involved in the control of apoptosis (Ham et al. 1995;Verheij et al. 1996;Bossy-Wetzel et al. 1997) and differentiation (Lord et al. 1993;Bohmann et al. 1994;Szabo et al. 1994;Patel and Sytkowski 1995). Although the mitogenic signaling pathways acting upstream of c-Jun are reasonably well understood, as is the basic cell cycle machinery, the connections between the two are still unclear (Cano and Mahadevan 1995;Karin and Hunter 1995).The core cell cycle clock itself operates by sequential activation and inactivation of a number of protein kinase complexes known as CDKs Sherr 1996). In G 1 , these kinases consist of cyclin D1, D2, or D3 associated with CDK4 or CDK6 and cyclin E-CDK2 and phosphorylate, among others, the retinoblastoma protein (pRb) (Weinberg 1995
The mouse skin has become the model of choice to study the regulation and function of AP-1 subunits in many physiological and pathological processes in vivo and in vitro. Genetically modi®ed mice, in vitro reconstituted skin equivalents and epidermal cell lines were established, in which AP-1-regulated genetic programs of cell proliferation, di erentiation and tumorigenesis can be analysed. Since the epidermis, as our interface with the environment, is subjected to radiation and injury, signal transduction pathways and critical AP-1 members regulating the mammalian stress response could be identi®ed. Regulated expression of important components of the cytokine network, cell surface receptors and proteases, which orchestrate the process of wound healing has been found to rely on AP-1 activity. Here we review our current knowledge on the function of AP-1 subunits and AP-1 target genes in these fascinating ®elds of skin physiology and pathology. Oncogene (2001) 20, 2413 ± 2423.
Interactions between mesenchymal and epithelial cells are responsible for organogenesis and tissue homeostasis. This mutual cross-talk involves cell surface proteins and soluble factors, which are mostly the result of regulated transcription. To elucidate dimer-specific functions of the AP-1 family of transcription factors, we reconstituted skin by combining primary human keratinocytes and mouse wild-type, c-jun(-/-), and junB(-/-) fibroblasts. We have discovered an antagonistic function of these AP-1 subunits in the fibroblast-mediated paracrine control of keratinocyte proliferation and differentiation, and traced this effect to the IL-1-dependent regulation of KGF and GM-CSF. These data suggest that the relative activation state of these AP-1 subunits in a non-cell-autonomous, transregulatory fashion directs regeneration of the epidermis and maintenance of tissue homeostasis in skin.
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