The proto-oncogene c-fos is the cellular homologue of v-fos originally isolated from murine osteosarcoma. Fos protein is a major component of the AP-1 transcription factor complex, which includes members of the jun family. Stable expression of c-fos in mice has been demonstrated in developing bones and teeth, haematopoietic cells, germ cells and in the central nervous system. It has been proposed that c-fos has an important role in signal transduction, cell proliferation and differentiation. We have previously demonstrated that overexpression of c-fos in transgenic and chimaeric mice specifically affects bone, cartilage and haematopoietic cell development. To understand better the function of c-fos in vivo, we used gene targeting in embryonic stem cells to generate cells and mice lacking c-fos. Here we report that heterozygous fos +/- mice appear normal, although females exhibit a distorted transmission frequency. All homozygous fos -/- mice are growth-retarded, develop osteopetrosis with deficiencies in bone remodelling and tooth eruption, and have altered haematopoiesis. These data define the c-Fos protein as an essential molecule for the development of specific cellular compartments.

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

No abstract

Mice lacking the AP‐1 transcription factor c‐jun die at mid‐gestation showing heart defects and impaired hepatogenesis. To inactivate c‐jun in hepatocytes, mice carrying a floxed c‐jun allele were generated. Perinatal liver‐specific c‐jun deletion caused reduced hepatocyte proliferation and decreased body size. After partial hepatectomy, half of the mutants died and liver regeneration was impaired. This phenotype was not present in mice lacking the N‐terminal phosphorylation sites of c‐Jun. The failure to regenerate was accompanied by increased cell death and lipid accumulation in hepatocytes. Moreover, cyclin‐dependent kinases and several cell cycle regulators were affected, resulting in inefficient G1–S phase progression. These studies identify c‐Jun as a critical regulator of hepatocyte proliferation and survival during liver development and regeneration.

The functions of JunB during myelopoiesis were studied in vivo. Transgenic mice specifically lacking JunB expression in the myeloid lineage (junB(-/-)Ubi-junB mice) develop a transplantable myeloproliferative disease eventually progressing to blast crisis, which resembles human chronic myeloid leukemia. Similarly, mice reconstituted with ES cell-derived junB-/- fetal liver cells also develop a myeloproliferative disease. In both cases, the absence of JunB expression results in increased numbers of granulocyte progenitors, which display enhanced GM-CSF-mediated proliferation and extended survival, associated with changes in the expression levels of the GM-CSFalpha receptor, the anti-apoptotic proteins Bcl2 and Bclx, and the cell cycle regulators p16(INK4a) and c-Jun. Importantly, ectopic expression of JunB fully reverts the immature and hyperproliferative phenotype of JunB-deficient myeloid cells. These results identify JunB as a key transcriptional regulator of myelopoiesis and a potential tumor suppressor gene.