Abstract
PDCD4 is a novel tumor suppressor to show multi-functions inhibiting cell growth, tumor invasion, metastasis, and inducing apoptosis. PDCD4 protein binds to the translation initiation factor eIF4A, some transcription factors, and many other factors and modulates the function of the binding partners. PDCD4 downregulation stimulates and PDCD4 upregulation inhibits the TPA-induced transformation of cells. However, PDCD4 gene mutations have not been found in tumor cells but gene expression was post transcriptionally downregulated by micro environmental factors such as growth factors and interleukins. In this review, we focus on the suppression mechanisms of PDCD4 protein that is induced by the tumor promotors EGF and TPA, and in the inflammatory conditions. PDCD4-protein is phosphorylated at 2 serines in the SCFβTRCP ubiquitin ligase binding sequences via EGF and/or TPA induced signaling pathway, ubiquitinated, by the ubiquitin ligase and degraded in the proteasome system. The PDCD4 protein synthesis is inhibited by microRNAs including miR21.
Highlights
12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF) are well known potent promotors for carcinogenesis [1,2]
In response to the tumor promotor TPA, P+ cells form colonies in agar plates, but P- cells do not. They showed that the down-regulation of Pdcd4 in P- cells resulted in acquisition of transformation sensitive phenotype (P+) and the up-regulation of Pdcd4 in the P+ type cells changed to P- type cells
Thereby, the eukaryotic translation initiation factor 4A (eIF4A) is included as a member in the translation initiation factor complex eukaryotic translation initiation factor 4F, functions as the RNA helicase to linearize the secondary structures in the 5 -untranslated region (5 -UTR) of mRNA and stimulated the cap-dependent translation
Summary
12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF) are well known potent promotors for carcinogenesis [1,2]. Colburn et al established the JB6 mouse epidermal cell lines, which are promotion sensitive (P+) and resistant (P-) to TPA-induced neoplastic transformation [3]. Activation protein-1 (AP-1), a trans-acting transcription factor, was shown to be stimulated in the promotion sensitive (P+), but not in the promotion resistant (P-) cells [4,5]. Experiments to find a suppressor of the neoplastic transformation induced by the tumor promotors resulted in Pdcd suppressing AP-1 activation and TPA-induced neoplastic transformation in the JB6 cells [6]. The mouse homolog was isolated as a gene that expression was up-regulated in the apoptosis [9] or down-regulated by topoisomerase inhibitors such as Camptothecin [10]. The gene is well conserved in species; for example, the homology between human and fish (elephant shark) is 72 % identical in the protein level. The expression of PDCD4-protein is often down-regulated in the tumors [17,18,19,20] but is maintained in high levels in a large number of tumors
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