Disease relevance of Pdcd4

• In response to the 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) mouse skin carcinogenesis protocol, K14-Pdcd4 mice showed significant reductions in papilloma formation, carcinoma incidence, and papilloma-to-carcinoma conversion frequency compared with wild-type mice [1].
• The transformation suppressor gene Pdcd4 (programmed cell death gene 4) inhibits the tumor-promoter mediated transformation of mouse keratinocytes and has recently been implicated as a potential tumor suppressor gene in the development of human lung cancer [2].
• We recently cloned the cDNA TIS (topoisomerase inhibitor-suppressed) in RVC lymphoma cells exposed to the topoisomerase inhibitors [3].
• Considering that topoisomerase I is an essential enzyme in mammalian cells, the TIS protein may have an important role in camptothecin toxicity [3].
• Among such clones, the MA-3 mRNA was induced in all apoptosis-inducible cell lines tested so far, including thymocytes, T cells, B cells and pheochromocytoma [4].

High impact information on Pdcd4

• The antisense-transfected cells were reverted to their initial P- phenotype by overexpression of a Pdcd4 sense fragment [5].
• To test the hypothesis that Pdcd4 inhibits tumor promoter-induced transformation, stable cell lines expressing antisense Pdcd4 were generated from parental P- cells [5].
• Pdcd4 mRNA was also expressed at greater levels in the less progressed keratinocytes of another mouse skin neoplastic progression series [5].
• In addition, both Pdcd4 and Pdcd4(D418A) bound to the middle region of eIF4G [6].
• The transformation suppressor Pdcd4 is a novel eukaryotic translation initiation factor 4A binding protein that inhibits translation [6].

Chemical compound and disease context of Pdcd4

• We also measured the induction of TIS genes by TPA and/or cycloheximide in Raw264.7 mouse macrophage cells and U937 human histiocytic lymphoma cells [7].

Biological context of Pdcd4

• Pdcd4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation [8].
• Whether Pdcd4 downregulation is necessary not only to induce transformation but also to maintain tumor phenotypes has not been determined previously [8].
• The Pdcd4 gene has originally been isolated in a search for genes that are activated in cells undergoing apoptosis [9].
• We show that Pdcd4 interferes with the phosphorylation of c-Jun by Jun N-terminal kinase (JNK) [2].
• The nucleotide sequence of the MA-3 cDNA predicted an amino acid (aa) sequence of 469 aa, which did not reveal significant similarity to any known proteins and functional aa motifs in databases [4].

Anatomical context of Pdcd4

• In vivo translation assays showed that Pdcd4 inhibited cap-dependent but not internal ribosome entry site (IRES)-dependent translation [6].
• A Northern blot analysis showed that the TIS was expressed in most mouse tissues; at the highest level in the liver and to less extent in the heart and skeletal muscle [3].
• The MA-3 mRNA was strongly expressed in the thymus although small amounts of the MA-3 mRNA were ubiquitously expressed in mouse adult tissues [4].
• TIS genes are rapidly and transiently induced by tetradecanoyl phorbol acetate in 3T3 cells [10].
• Our analysis here of the expression of these genes in the testis of the cAMP-responsive element modulator (CREM)-null mouse revealed that 54 TISP genes are under the transcriptional regulation of CREM [11].

Associations of Pdcd4 with chemical compounds

• We show that the Pdcd4 protein is a predominantly nuclear protein under normal growth conditions and that it is exported from the nucleus by a leptomycin B-sensitive mechanism upon serum withdrawal [9].
• After the transient stresses, Triton (X-100)insoluble (TIS) fractions were isolated from the cells and analysed by electrophoresis and immunoblotting [12].
• Aerosol delivery of urocanic acid-modified chitosan/programmed cell death 4 complex regulated apoptosis, cell cycle, and angiogenesis in lungs of K-ras null mice [13].

Co-localisations of Pdcd4

• Immunofluorescent confocal microscopy showed that Pdcd4 colocalizes with eIF4A in the cytoplasm. eIF4A is an ATP-dependent RNA helicase needed to unwind 5' mRNA secondary structure [6].

Regulatory relationships of Pdcd4

• Thus, Pdcd4 suppresses tumor phenotype by inhibiting AP-1-dependent transcription, possibly through inhibiting c-Jun and c-Fos activation [8].
• Pdcd4 directly inhibits the helicase activity of eukaryotic translation initiation factor 4A, a component of the translation initiation complex [1].
• Pdcd4 inhibited by 46% TPA-induced activator protein-1 (AP-1)-dependent transcription, an event required for tumorigenesis [1].

Other interactions of Pdcd4

• In a Gal4 fusion assay, Pdcd4 specifically inhibited activation of c-Jun and c-Fos activation domains, but did not inhibit activation of JunB, JunD, Fra-1, or Fra-2 [8].
• The Pdcd4 protein has weak homology to the eucaryotic translation initiation factor eIF4G and has been shown to interact with certain translation initiation factors [9].
• These results indicate that Pdcd4 functions as a transformation suppressor, possibly through inhibiting AP-1 activation in combination with other factors such as enhancing NF-kappaB activation [14].
• Independent of these studies, the Pdcd4 gene has been implicated in the suppression of tumor-promoter-mediated transformation of keratinocytes and as a downstream target of Myb in hematopoietic cells [9].

Analytical, diagnostic and therapeutic context of Pdcd4

• In vivo induction of the TIS genes (TIS21, -8 and -1) by intraperitoneal injection of TPA was dramatic only at the needle contact site, i.e. in the abdominal muscle, not in the thigh muscle [7].

References