Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation

Abstract

An mRNA differential display comparison of mouse JB6 promotionsensitive (P؉) and -resistant (P؊) cells identified a novel gene product that inhibits neoplastic transformation. The JB6 P؉ and P؊ cells are genetic variants that differ in their transformation response to tumor promoters; P؉ cells form anchorage-independent colonies that are tumorigenic, and P؊ cells do not. A differentially displayed fragment, A7-1, was preferentially expressed in P؊ cells at levels >10-fold those in P؉ cells, making its mRNA a candidate inhibitor of neoplastic transformation. An A7-1 cDNA was isolated that was identical to murine Pdcd4 gene cDNAs, also known as MA-3 or TIS, and analogous to human H731 and 197͞15a. Until now, the function of the Pdcd4 protein has been unknown. Paralleling the mRNA levels, Pdcd4 protein levels were greater in P؊ than in P؉ cells. Pdcd4 mRNA was also expressed at greater levels in the less progressed keratinocytes of another mouse skin neoplastic progression series. To test the hypothesis that Pdcd4 inhibits tumor promoter-induced transformation, stable cell lines expressing antisense Pdcd4 were generated from parental P؊ cells. The reduction of Pdcd4 proteins in antisense lines was accompanied by acquisition of a transformation-sensitive (P؉) phenotype. The antisense-transfected cells were reverted to their initial P؊ phenotype by overexpression of a Pdcd4 sense fragment. These observations demonstrate that the Pdcd4 protein inhibits neoplastic transformation.

Tumor suppressor Pdcd4 inhibits invasion/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-transcription factors

“…Pdcd4 has been identified as a suppressor of malignant transformation (Cmarik et al, 1999;Yang et al, 2001aYang et al, , b, 2003a, tumorigenesis and tumor Figure 3 u-PAR promoter activity is downregulated by Pdcd4 overexpression and upregulated by knockdown of Pdcd4. (a) GEO cells were transfected with 0.08 mg of a luciferase-reporter plasmid driven by À398 bp of the wild-type u-PAR promoter (pGl3u-PAR-398), 0.02 mg of a renilla vector as an internal control, together with an siRNA specific for Pdcd4 or an unspecific (scrambled) siRNA at a final concentration of 40 nM.…”

“…Pdcd4 has been described recently as a new tumor suppressor gene, its overexpression being sufficient to inhibit 12-O-Tetradecanoylphorbol 13-acetate 4b,9a, 12b,13a,20-Pentahydroxytiglia-1,6-dien-3-one 12-tetradecanoate 13-acetate (TPA)-induced neoplastic transformation (Cmarik et al, 1999;Yang et al, 2001a), as well as tumor promotion and progression to carcinomas in a transgenic mouse model (Jansen et al, 2005). It was identified in the JB6 mouse epidermal clonal genetic variant cell system as a 64 kDa protein, being preferentially expressed in tumor-promoter-resistant cells and suppressed in promotion-sensitive cells undergoing neoplastic transformation (Cmarik et al, 1999).…”

“…It was identified in the JB6 mouse epidermal clonal genetic variant cell system as a 64 kDa protein, being preferentially expressed in tumor-promoter-resistant cells and suppressed in promotion-sensitive cells undergoing neoplastic transformation (Cmarik et al, 1999). The pdcd4 cDNA is identical to murine MA-3 and TIS genes (Shibahara et al, 1995;Onishi and Kizaki, 1996), and there is a high homology to the human genes H731 and 197/15 (Azzoni et al, 1998;Yoshinaga et al, 1999).…”

Pdcd4 directly binds the coding region of c-myb mRNA and suppresses its translation

“…Pdcd4 was originally identified as a gene whose expression is increased during apoptosis (Shibahara et al, 1995), but has now been implicated as a tumor suppressor in a broad spectrum of human tumors. Pdcd4 was initially shown to suppress tumor development in an in vitro mouse keratinocyte model of tumor promotion (Cmarik et al, 1999). More recently, decreased expression of Pdcd4 has been implicated in the development and progression of human lung, colon, liver and breast cancer (Chen et al, 2003;Afonja et al, 2004;Zhang et al, 2006;Mudduluru et al, 2007).…”

Programmed Cell Death 4 inhibits breast cancer cell invasion by increasing Tissue Inhibitor of Metalloproteinases-2 expression

“…[8] demonstrated that inhibition of COX-2 by the selective inhibitor NS398 increased the mRNA expression of Programmed Cell Death 4 (PDCD4) in colon cancer cells. PDCD4 suppresses the in vitro transformation of mouse keratinocytes induced by 12-Otetradecanoylphorbol-13-acetate (TPA) [9,10] and the promotion and progression of skin carcinogenesis in response to 7,12-dimethylbenz(a)anthracene/TPA in animal models [11]. PDCD4 interacts with translation initiation factors eIF4A and eIF4G and inhibits AP-1 transactivation [9,12].…”