Disease relevance of Tpx2

• These results show that increased p100/p52 disrupts normal ductal development and provides insight into the mechanism by which this may contribute to human breast cancer [1].
• Recently, the expression of a tudor and staphylococcal nuclease-like domains containing protein p100 was found to be increased in mammary epithelial cells during lactation in response to lactogenic hormones. p100 was initially identified as a transcriptional coactivator of the Epstein-Barr virus nuclear antigen 2 [2].

High impact information on Tpx2

• NF-kappaB2/p100 cleavage was abrogated in B cells from A/WySnJ mice possessing a mutant BR3 gene, but not in TACI or BCMA null B cells [3].
• Biochemical studies indicated involvement of a cell-intrinsic mechanism in which NF-kappaB2 (p100) limits nuclear translocation of NF-kappaB1-RelA and thereby functions as a regulatory 'brake' for the activation of naive T cells [4].
• Thus, Pim-1 and p100 appear to be components of a novel signal transduction pathway affecting c-Myb activity, linking all three to the cytokine-regulated control of hematopoietic cell growth, differentiation, and apoptosis [5].
• Conversely, p100-deficient osteoclast precursors show enhanced sensitivity to RANKL [6].
• Finally, we show that TNF increases p100 levels, resulting in the specific inhibition of RelB DNA binding via the C-terminus of p100 [7].

Biological context of Tpx2

• Similarities suggested that p100 is also an ETS domain protein, possibly Elf-1 [8].
• After multiple pregnancies the p100 transgenics exhibited a ductal thickening accompanied by small hyperplastic foci [1].
• Based on the phenotype of mice deficient in various components of the LTbetaR-induced activation of p100 processing, we conclude that this pathway is critically involved in the function of stromal cells during the generation of secondary lymphoid organ microarchitectures [9].
• Additionally, induction of p100 phosphorylation can be blocked by a protein synthesis inhibitor, suggesting the requirement of de novo protein synthesis [10].
• Instead, trichostatin A enhances p52 acetylation and increases p52 protein level by enhancing p100 processing [11].

Anatomical context of Tpx2

• In tumors from mice expressing the polyoma middle T oncoprotein (PyVT) in the mammary gland, increased levels of p100/p52 were present at the time of tumor development [1].
• These data lead us to propose that the p100 is a transmembrane protein, the expression of which in the plasma membrane is dependent on the association or presence of Thy-1 molecule [12].
• The p100 coactivator, first identified as a coactivator of the Epstein-Barr virus-encoded transcription factor, EBNA-2, in cultured cells, interacts with a number of transcription factors [13].
• Using two antibodies against independent parts of the protein, p100 immunoreactivity was localised to mammary epithelial cells, and was enriched in both nuclei and endoplasmic reticulum/organelle fractions [13].
• This effect coincides with an inhibition of the phosphorylation of a 100-kilodalton protein (p100) in epidermal cytosol in vitro, which has been identified as elongation factor 2 (EF-2) of protein biosynthesis [14].

Associations of Tpx2 with chemical compounds

• Mutation of either serine 866 or serine 870 abolishes the beta-TrCP recruitment and ubiquitination of p100 [10].
• This is the first report that trichostatin A, a HDAC inhibitor, activates p100 processing and relieves the repression of p52 acetylation [11].

Analytical, diagnostic and therapeutic context of Tpx2

• To assess the role of the precursor in vivo, we generated, by gene targeting, mice lacking p100 but still containing a functional p52 protein [15].
• Indeed, further in vitro experiments established that s-rIkappaB DC undergo efficient maturation upon prolonged contact with activated T cells via the alternative pathway of NF-kappaB activation triggered at least partly by lymphotoxin beta receptor ligation and involving processing of p100/RelB complexes [16].
• Tudor and nuclease-like domains containing protein p100 function as coactivators for signal transducer and activator of transcription 5 [2].

References