Deregulated expression of human c-jun transforms primary rat embryo cells in cooperation with an activated c-Ha-ras gene and transforms rat-1a cells as a single gene.

Abstract

While the ability of the retroviral oncogene V-jun to transform chicken cells led to its discovery, the oncogenic potential of its cellular homologue, c-jun, which encodes a transcription factor, is unknown. We isolated a 1070-base-pair cDNA clone containing the unmutated entire open reading frame of c-jun from a human small cell lung cancer line. This cDNA as well as a 5.6-kilobase normal human genomic DNA fragment containing the c-jun gene were placed under the control of retroviral long terminal repeats and introduced into primary rat embryo cells (RECs), with or without other oncogenes, and into an immortal rat fibroblast cell line, Rat-1a, as a single gene. In Rat-1a cells the expression of human c-jun mRNA was associated with the ability to clone in soft agarose and form tumors in nude mice. When the c-jun cDNA or genomic DNA constructs were introduced into RECs, no foci of transformed cells were seen with c-jun alone or c-jun cotransfected with deregulated c-myc or L-myc protooncogenes. However, cotransfection of the c-jun constructs with an activated human c-Ha-ras gene led to foci of transformed cells which gave rise to immortalized cell lines that cloned in soft agarose and formed tumors in nude mice. Furthermore, formation of foci of transformed RECs by the c-jun/ras combination was augmented 3-fold by the tumor promoter phorbol 12-tetradecanoate 13-acetate. We conclude that deregulated expression of human c-jun can participate in malignant transformation of normal mammalian cells.

Cooperation between GLI and JUN enhances transcription of JUN and selected GLI target genes

“…Potential GLI-binding sites were mutated at positions 6 and 7 to G and AP-1-binding sites JUNBS1 and JUNBS2 were mutated as described in Angel et al (1988b) and Stein et al (1992) using the QuickChange site-directed mutagenesis kit (Stratagene, La Jolla, CA, USA). GLI1, GLI2, GLI2act, GLI3act, JUN, SUFU expression constructs have been described previously (Schutte et al, 1989;Kogerman et al, 1999;Eichberger et al, 2008).…”

Directed mutation of the basic domain of v-Jun alters DNA binding specificity and abolishes its oncogenic activity in chicken embryo fibroblasts

“…Overexpression of viral Jun induces cell transformation in both avian and mammalian cell culture models (Bos et al, 1990;Castellazzi et al, 1990;SchuÈ tte et al, 1989;Wong et al, 1992). In chicken embryo ®broblasts (CEF), signi®cant di erences in transforming e ciency occur between v-Jun and its cellular counterpart, c-Jun (Bos et al, 1990;Castellazzi et al, 1990;Wong et al, 1992).…”

“…In rodent cells, transformation resulting from overexpression of c-Jun has been correlated to increases in DNA binding and transcriptional regulatory activity (SchuÈ tte et al, 1989). Indeed, mutations which a ect either DNA binding or transcriptional activation abolish transforming activity (Alani et al, 1991;Brown et al, 1993;GrangerSchnarr et al, 1992;Lloyd et al, 1991).…”

cJun overexpression in MCF-7 breast cancer cells produces a tumorigenic, invasive and hormone resistant phenotype

“…Deregulated expression of cJun can lead to malignant transformation of immortalized rat ®broblasts while transformation of primary rat embryo cells required co-expression of an activated c-Ha-ras (Alani et al, 1991;Schutte et al, 1989). In chicken embryo ®broblasts, cJun can induce cellular transformation by itself (Suzuki et al, 1991;Castellazzi et al, 1990).…”

“…To our knowledge, this is the ®rst reported example of cJun overexpression inducing human cancer cells to form tumors in nude mice. c-jun has been demonstrated to transform primary avian or rodent cells as a single gene or in cooperation with an activated ras gene (Alani et al, 1991;Schutte et al, 1989). The mechanism by which cJun transforms cells remains unclear but presumably involves the regulation of gene expression.…”