Increase in AP-1 activity is a general event in thyroid cell transformation in vitro and in vivo

Abstract

We have recently reported that neoplastic transformation of two rat thyroid epithelial cell lines by retroviruses carrying the v-mos and v-ras Ki oncogenes is associated with a drastic increase of AP-1 activity. The most important eects were represented by the dramatic junB and fra-1 gene induction, which was abolished by the block of the transformation-induced HMGI-C protein synthesis. Here, we have further characterized the transformation-dependent AP-1 activity, by analysing the expression of dierent jun-and fos-related components, in rat thyroid cell lines transformed by several oncogenes, in human thyroid carcinoma cell lines, and in naturally occurring human thyroid tumours. A signi®cant increase of Fra-1 and JunB protein levels was detected in all oncogene transformed rat thyroid cell lines. Fra-1 gene induction was demonstrated to occur also in human thyroid carcinoma cell lines and tissues. Conversely, cJun and JunD proteins, rather than JunB, accumulated in human thyroid carcinoma cell lines. An induction of AP-1 target genes was also detected both in rat and human thyroid transformed cell lines. Therefore, in vivo and in vitro thyroid cell transformation is associated with important compositional changes in the AP-1 complex and an increased transcriptional activity.

Adenovirus-mediated suppression of HMGI(Y) protein synthesis as potential therapy of human malignant neoplasias

“…Therefore, interaction between HMGI(Y) proteins and AP-1 transcriptional complex may be required for the activation of genes whose expression is associated with malignant transformation. This hypothesis is consistent with lack of expression of the tumor-associated genes VEGF, collagenase I, and stromelysin, which are AP-1-dependent, in thyroid cell lines in which HMGI protein expression has been suppressed (26,27).…”

An increased high-mobility group A2 expression level is associated with malignant phenotype in pancreatic exocrine tissue

“…The interaction between HMGA2 and the AP-1 transcriptional complex is considered to be responsible for the activation of genes whose expressions are associated with carcinogenesis (Vallone et al, 1997), since thyroid neoplastic transformation is associated with a drastic increase in AP-1 activity. This AP-1 activity is blocked by suppressing HMGA protein synthesis in vitro (Battista et al, 1998). The absence or decreased AP-1 transcriptional activity, which is directly or indirectly regulated by HMGA proteins, would inhibit the expression of AP-1-dependent genes, such as those of vascular endothelial growth factor (VEGF), collagenase I (matrix metalloproteinase-1; MMP-1), and stromelisin (MMP-3), which are essential for neoplastic transformation of cells (Vallone et al, 1997).…”

Attenuated expression of the serum responsive T1 gene in ras transformed fibroblasts due to the inhibition of c-fos gene activity

“…Proliferin is an angiogenic factor and might be involved in the neovascularization of tumors. Other AP-1 responsive genes encoding proteins involved in tumorigenesis such as the proteases stromelysin and interstitial collagenase as well the angiogenic growth factor VEGF are constitutively expressed at high levels in many transformed cell lines and in tumors where their activation might be controlled by elevated levels of Fra-1 containing AP-1 (Battista et al, 1998;Vallone et al, 1997).…”