Disease relevance of POLDIP3

• Inhibition of ShcA isoforms p46/p52Shc enhances HIV-1 replication in CD4+ T-lymphocytes [1].
• Enhanced expression of p46 Shc in the nucleus and p52 Shc in the cytoplasm of human gastric cancer [2].
• The p46 protein, which electrophoresed as a doublet was the main component immunoprecipitated from extract of a differentiated human pancreatic adenocarcinoma as well as from the extracts of two pancreatic cell lines, BxPC-3 and SOJ-6 [3].
• Previously an Mr 46,000 protein (named p46) was shown to be induced in the culture medium of human hepatoblastoma cells, Huh-6 Cl-5, treated with 12-O-tetradecanoyl phorbol-13-acetate (TPA) [4].
• In situ analysis of the enzymatic activity of individual HCMV polypeptides, separated in a DNA-containing polyacrylamide gel, has shown that the DNase activity present in purified virions is mainly associated with a polypeptide of 46,000 dalton MW (p46) [5].

High impact information on POLDIP3

• These data strongly suggest that NKp44 functions as a triggering receptor selectively expressed by activated NK cells that, together with p46, may be involved in the process of non-MHC-restricted lysis [6].
• Both the unique cellular distribution and functional capability of p46 molecules suggest a possible role in the mechanisms of non-major histocompatibility complex-restricted cytolysis mediated by human NK cells [7].
• The p46 and p54 isoforms of c-Jun amino-terminal kinase (JNKs) were identified as HNE targets and were activated by this aldehyde [8].
• LPS treatment of RAW 264.7 cells, murine bone marrow-derived macrophages, and the human monocyte cell line THP-1 resulted in rapid activation of the p46 and p54 isoforms of JNK [9].
• The loss of phosphorylation is not due to changes in cell cycle distribution and/or apoptosis and is mediated independent of either p46/54(JNK) or MSK-1/2 inhibition [10].

Biological context of POLDIP3

• We find that serines 383 and 385 of human SKAR are insulin-stimulated and rapamycin-sensitive S6K1 phosphorylation sites [11].
• CONCLUSIONS: We have identified a novel and specific target of S6K1, SKAR, which regulates cell growth [11].
• Furthermore, RNAi-mediated reduction of SKAR decreases cell size [11].
• The homology of SKAR to the Aly/REF family links S6K1 with mRNA biogenesis in the control of cell growth [11].
• However, immunofluorescence experiments performed after transient transfections showed that p46 and p33/32 were also located in vivo into the nucleus [12].

Anatomical context of POLDIP3

• BAB281 identified a novel NK cell-specific surface molecule of 46 kD (p46) that is expressed by all resting or activated NK cells [7].
• The p46 isoforms of dually phosphorylated JNKs were detected in the nuclei of both normal and AT fibroblasts following exposure to ionizing radiation or sham radiation [13].
• Thus, Env p46-specific CD4(+) T cells can be detected by tetrameric Mamu-DR*W201-p46 complex staining of PBMCs in both SHIV-infected and vaccinated rhesus monkeys [14].
• Furthermore, not only p52 Shc expression in the cytoplasm but also p46 Shc expression in the nucleus was much higher in gastric cancer than in the adjacent normal mucosa [2].
• For further characterization of p46, Huh-7 Cl-4, another line of well differentiated liver cells, was incubated in the presence and absence of TPA, and proteins were labeled with [35S]methionine, and the proteins secreted into the medium were analyzed by one- and two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis [4].

Associations of POLDIP3 with chemical compounds

• When the labeled proteins were analyzed by two-dimensional polyacrylamide gel electrophoresis, p46 was composed of three isoproteins which had different isoelectric points [15].
• The induction of p46 secretion involved de novo RNA synthesis, since actinomycin D (1 microgram/ml) completely and selectively blocked the incorporation of [35S]-methionine into the protein. "Pulse-chase" experiments indicated that p46 was not a degradation product induced by these potent tumor promoters [15].
• Aptamer KDI1 did not summarily block the EGF receptor tyrosine kinase activity but selectively interfered with the EGF-induced phosphorylation of the tyrosine residues 845, 1068, and 1148 as well as the phosphorylation of tyrosine 317 of p46 Shc [16].
• Treatment of the transfected cells with cisplatin, staurosporine, paclitaxel and doxorubicine showed that BAG-1 p50, p46 and p33 isoforms enhanced the resistance to apoptosis [17].
• Quantitative analysis of p40/p46 and p69/p71 forms of 2',5'-oligoadenylate synthetase mRNA by competitive PCR and its clinical application [18].

Physical interactions of POLDIP3

• RESULTS: Here we identify SKAR as a novel and specific binding partner and substrate of S6K1 but not S6K2 [11].

Other interactions of POLDIP3

• SKAR is a specific target of S6 kinase 1 in cell growth control [11].

Analytical, diagnostic and therapeutic context of POLDIP3

• Irradiation of intact cells in the presence of [alpha-32P]BzATP followed by SDS-PAGE and autoradiography revealed two labeled proteins with molecular masses of 46 and 96 kDa (p46 and p96) [19].
• In contrast, immunohistochemical and Western blot analyses revealed that p52 Shc was detected in the cytoplasmic fractions obtained from gastric normal mucosa and cancer, while p46 Shc expression was observed in the nuclear fractions from gastric normal mucosa and cancer [2].
• Using Shc immunoprecipitation and anti-phosphotyrosine immunoblotting analysis, we found a strong correlation between the level of ErbB2 overexpression (r = 0.91, p < 0.0002) and PY-ErbB2 levels (r = 0.89, p = 0.0005) compared with the level of tyrosine phosphorylation of the p52 and p46 Shc isoforms [20].
• Protein sequence analysis of the peptides from p46 revealed a high homology with human enolase, an important glycolytic enzyme [21].

References