The Transactivating Domain of the c-Jun Proto-Oncoprotein Is Required for Cotransformation of Rat Embryo Cells

Abstract

The nuclear phosphoprotein c-Jun, encoded by the proto-oncogene c-jun, is a major component of the AP-1 complex. A potent transcriptional regulator, c-jun is also able to transform normal rat embryo cells in cooperation with an activated c-Ha-ras gene. By deletion analysis, we identified the regions of c-Jun encoding transformation and transactivation functions. Our studies indicate that there is a direct correlation between the ability of the c-Jun protein to activate transcription and cotransform rat embryo cells. The regions involved in these functions include the conserved leucine zipper/DNA binding domain and an effector domain near its N terminus. This N-terminal region spans amino acids 61 to 146 of the c-Jun protein and is highly conserved among all Jun family members. These results support the hypothesis that c-Jun transforms cells by stimulating the expression of transformation-mediating genes.

An Approach to Derive Functional Peptide Inhibitors of Transcription Factor Activity

“… 12 − 17 cJun binds to 12-O-tetradecanoylphorbol-13-acetate response elements (TREs), directly influencing cellular processes such as differentiation, proliferation, and survival. 13 − 15 , 18 Dysregulation of these functions therefore promotes hallmark cancer cell behavior, rendering cJun a focal point for cancer therapy.…”

“…12−17 cJun binds to 12-O-tetradecanoylphorbol-13acetate response elements (TREs), directly influencing cellular processes such as differentiation, proliferation, and survival. [13][14][15]18 Dysregulation of these functions therefore promotes hallmark cancer cell behavior, rendering cJun a focal point for cancer therapy. Many rational design approaches, library screens, and selection systems exist and have resulted in the successful identification of molecules capable of binding to given TF targets, but a key challenge remains in ensuring that target binding will translate into ablation of function.…”

“…In the search for functionally active TF antagonists, we have taken inspiration from the basic leucine-zipper (bZIP) DNA binding mechanism. Dimerization of this domain is driven by the formation of a leucine zipper (LZ), with DNA binding domains (DBDs) extending toward the N-terminus of these helices to facilitate DNA sequence recognition (Figure A). − Our efforts here focus on developing molecules that inhibit the validated oncogenic transcriptional regulator cJun, a member of the activator protein-1 family and an exemplar for bZIP proteins in general. − cJun binds to 12-O-tetradecanoylphorbol-13-acetate response elements (TREs), directly influencing cellular processes such as differentiation, proliferation, and survival. − , Dysregulation of these functions therefore promotes hallmark cancer cell behavior, rendering cJun a focal point for cancer therapy.…”