Alternative titles; symbols
HGNC Approved Gene Symbol: PDCD4
Cytogenetic location: 10q25.2 Genomic coordinates (GRCh38) : 10:110,871,928-110,900,006 (from NCBI)
By screening a glioma cDNA expression library with antibodies raised against a nuclear protein, Matsuhashi et al. (1997) cloned PDCD4, which they designated H731. The deduced 458-amino acid protein has a calculated molecular mass of 50.6 kD. PDCD4 is an acidic protein with characteristics of a nuclear nonhistone protein. It contains 2 overlapping GxGxxG nucleotide-binding motifs, which are characteristic of protein kinases, but it does not have a kinase catalytic domain. PDCD4 also has several putative serine and threonine phosphorylation sites. Northern blot analysis detected transcripts of about 2.7 and 3.8 kb in HeLa cell total RNA. Recombinant PDCD4 expressed in E. coli resulted in proteins with apparent molecular masses of 56 and 37 kD. The 37-kD truncated protein was synthesized from val127, reading the val codon as an f-met initiation codon.
Yoshinaga et al. (1999) found that PDCD4 accumulated in the nuclei of confluent or quiescent normal fetal lung fibroblasts, but it was overproduced and localized in the cytoplasm during the cell cycle in tumor cell lines. Immunohistologic analysis revealed that PDCD4 was highly expressed in bladder carcinoma and breast carcinoma tissues compared with normal tissues. PDCD4 was also abundantly expressed in the small duct epithelial cells of normal mammary gland.
By Northern blot and Western blot analyses, Kang et al. (2002) determined that expression of both the PDCD4 transcript and protein was upregulated in senescent diploid fibroblasts compared with cells in log phase growth. Yeast 2-hybrid analysis showed that the C terminus of PDCD4 could interact with a component of the 40S ribosome complex, RPS13 (180476), and with RPL5 (603634) and TI-227H. In vitro binding assays confirmed the interaction between PDCD4 and RPS13. In vitro pull-down assays also showed that PDCD4 interacted with EIF4G (600495), but not with EIF4E (133440). Furthermore, PDCD4 localized to polysome fractions of fractionated HeLa cells. Kang et al. (2002) concluded that PDCD4 may regulate EIF4G-dependent translation through direct interaction with EIF4G and RPS13 in senescent fibroblasts.
Dorrello et al. (2006) found that the tumor suppressor PDCD4 inhibits the translation initiation factor EIF4A (see 602641), an RNA helicase that catalyzes the unwinding of secondary structure at the 5-prime untranslated region of mRNAs. In response to mitogens, PDCD4 was rapidly phosphorylated on ser67 by the protein kinase S6K1 (608938) and subsequently degraded via the ubiquitin ligase SCF-beta(TRCP) (603482). Expression in cultured cells of a stable PDCD4 mutant that was unable to bind beta-TRCP inhibited translation of an mRNA with a structured 5-prime untranslated region, resulted in smaller cell size, and slowed down cell cycle progression. Dorrello et al. (2006) proposed that regulated degradation of PDCD4 in response to mitogens allows efficient protein synthesis and consequently cell growth.
PDCD4 contains 2 tandem MA3 domains consisting of conserved alpha-helical hairpins. Using x-ray crystallography, NMR, and surface plasmon resonance, Suzuki et al. (2008) found that both MA3 domains of human PDCD4 were structurally and functionally similar and bound specifically to the N-terminal domain of EIF4A using similar binding interfaces. The MA3 domains of PDCD4 competed with the MA3 domain of EIF4G and RNA for EIF4A binding. Suzuki et al. (2008) concluded that PDCD4 inhibits translation initiation by displacing EIF4G and RNA from EIF4A. They proposed that the PDCD4 MA3 domains act synergistically to form a tighter and more stable complex with EIF4A, explaining the need for 2 tandem MA3 domains.
Davis et al. (2008) demonstrated that induction of a contractile phenotype in human vascular smooth muscle cells by TGF-beta (190180) and BMPs (see 112264) is mediated by miR21 (611020). miR21 downregulates PDCD4, which in turn acts as a negative regulator of smooth muscle contractile genes. Davis et al. (2008) concluded that PDCD4 is a functional target of miR21 involved in the BMP-mediated induction of smooth muscle cell markers in vascular smooth muscle cells.
Asangani et al. (2008) identified an miR21 target sequence in the 3-prime UTR of PDCD4 and confirmed binding and inhibition of PDCD4 by miR21 using reporter gene assays. They observed an inverse correlation between miR21 and PDCD4 expression in 10 colorectal cell lines and in 22 colorectal cancer tissues and matched normal controls. Transfection of RKO human colorectal cancer cells with anti-miR21 increased PDCD4 protein concentration, reduced the invasive potential of RKO cells in 3-dimensional gels, and reduced intravasation and lung metastasis of RKO cells in a chicken embryo metastasis assay. Overexpression of miR21 reduced expression of PDCD4 protein, but not mRNA, in Colo206f cells.
By FISH, Soejima et al. (1999) mapped the PDCD4 gene to chromosome 10q24.
Asangani, I. A., Rasheed, S. A. K., Nikolova, D. A., Leupold, J. H., Colburn, N. H., Post, S., Allgayer, H. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27: 2128-2136, 2008. [PubMed: 17968323] [Full Text: https://doi.org/10.1038/sj.onc.1210856]
Davis, B. N., Hilyard, A. C., Lagna, G., Hata, A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454: 56-61, 2008. [PubMed: 18548003] [Full Text: https://doi.org/10.1038/nature07086]
Dorrello, N. V., Peschiaroli, A., Guardavaccaro, D., Colburn, N. H., Sherman, N. E., Pagano, M. S6K1- and beta-TRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 314: 467-471, 2006. [PubMed: 17053147] [Full Text: https://doi.org/10.1126/science.1130276]
Kang, M.-J., Ahn, H.-S., Lee, J.-Y., Matsuhashi, S., Park, W.-Y. Up-regulation of PDCD4 in senescent human diploid fibroblasts. Biochem. Biophys. Res. Commun. 293: 617-621, 2002. [PubMed: 12054647] [Full Text: https://doi.org/10.1016/S0006-291X(02)00264-4]
Matsuhashi, S., Yoshinaga, H., Yatsuki, H., Tsugita, A., Hori, K. Isolation of a novel gene from a human cell line with Pr-28 MAb which recognizes a nuclear antigen involved in the cell cycle. Res. Commun. Biochem. Cell Molec. Biol. 1: 109-120, 1997.
Soejima, H., Miyoshi, O., Yoshinaga, H., Masaki, Z., Ozaki, I., Kajiwara, S., Niikawa, N., Matsuhashi, S., Mukai, T. Assignment of the programmed cell death 4 gene (PDCD4) to human chromosome band 10q24 by in situ hybridization. Cytogenet. Cell Genet. 87: 113-114, 1999. [PubMed: 10640828] [Full Text: https://doi.org/10.1159/000015408]
Suzuki, C., Garces, R. G., Edmonds, K. A., Hiller, S., Hyberts, S. G., Marintchev, A., Wagner, G. PDCD4 inhibits translation initiation by binding to eIF4A using both its MA3 domains. Proc. Nat. Acad. Sci. 105: 3274-3279, 2008. [PubMed: 18296639] [Full Text: https://doi.org/10.1073/pnas.0712235105]
Yoshinaga, H., Matsuhashi, S., Fujiyama, C., Masaki, Z. Novel human PDCD4 (H731) gene expressed in proliferative cells is expressed in the small duct epithelial cells of the breast as revealed by an anti-H731 antibody. Path. Int. 49: 1067-1077, 1999.