The proto-oncogene c-fos increases the sensitivity of keratinocytes to apoptosis

Abstract

In human skin, most studies have suggested a role of cfos or c-fos related genes in keratinocyte dierentiation. The aim of our work was to more directly address this question by transfecting more or less dierentiated keratinocyte cell lines (A431 and HaCaT) with constitutive expression vectors for c-Fos or c-Fos+c-Jun. Our results showed that c-Fos expression decreased keratinocyte growth, yet addition of c-Jun seemed to revert this c-Fos induced growth inhibition. Whereas no obvious dierentiation program was turned on by c-Fos or c-Fos+c-Jun expression in our tissular model, apoptotic ®gures were observed and con®rmed by in situ DNA fragmentation studies. These results do not rule out a role of c-Fos in keratinocyte dierentiation but may indicate that the cell lines we used have reached an irreversible state of transformation so that they no longer respond to dierentiation signals and rather die from apoptosis. These data add further evidence in favor of a role of c-Fos in epidermal homeostasis.

Conversion of HPV 18 positive non-tumorigenic HeLa-fibroblast hybrids to invasive growth involves loss of TNF-α mediated repression of viral transcription and modification of the AP-1 transcription complex

“…Again, re-incubation of the same ®lter with a b-actin speci®c antibody con®rmed equal protein loading. Although it has been reported that constitutive over-expression of c-fos increases the sensitivity of cells to undergo apoptosis (Mils et al, 1997), no apparent correlation between the c-Fos levels and the appearance of apoptotic ®gures such as membrane blebbing or perinuclear chromatin condensation (Cohen, 1993) have been noted ( Figure 5). The phase-contrast microscopy depicts the cell morphology of three dierent clones (further designated as`clone 1, 2 and 5') in comparison with non-transfected`444'-cells, their tumorigenic segregants (`CGL3') and the parental HeLa cells.…”

The proto-oncoprotein c-Fos negatively regulates hepatocellular tumorigenesis

“…Since various cell types show a proapoptotic function of c-Fos (Smeyne et al, 1993;Marti et al, 1994;Hu et al, 1996;Preston et al, 1996;Hafezi et al, 1997;Mils et al, 1997;Buttyan et al, 1988), the AP-1 activity containing this critical factor could therefore have broad clinical relevance. In this light, the role of c-Fos appears to be of apparent significance in malignant hepatocytes that exhibit activation of Ras, either through mutations in this central effector protein itself or through the constitutive induction due to the hyperstimulation of receptor tyrosine kinases.…”

“…Similarly, continuous expression of c-Fos after light exposure leads to massive apoptosis of photoreceptors in the retina (Hafezi et al, 1997). Moreover, stimulation of cell death by exogenous expression of c-Fos has been reported in keratinocytes (Mils et al, 1997), colon carcinoma cells (Preston et al, 1996) and in pro-B cells with nonfunctional Ag receptor (Hu et al, 1996).…”

Identification of a C-terminal tripeptide motif involved in the control of rapid proteasomal degradation of c-Fos proto-oncoprotein during the G0-to-S phase transition

“…For Northern blotting experiments, total cell RNA was puri®ed using the RNAplus kit from Bioprobe according to the supplier's speci®cations. Northern blotting analysis conditions and cDNA probes were described in Mils et al (1997). Balb/c 3T3 cell c-fos mRNA was detected with a mouse-speci®c probe (Plasmid PM381 in ref.…”