Disease relevance of PPP5C

• If hypoxia is prolonged, the expression of PP5 is increased due to the activation of a transcriptional activator, which was identified as hypoxia-inducible factor-1 [1].
• In ERalpha-positive breast cancer MCF7 cells, estrogen- and epidermal growth factor-dependent phosphorylation of ERalpha on serine residue 118, a major phosphorylation site of the receptor, was reduced by expressing PP5 but enhanced by PP5 antisense oligonucleotide [2].
• Therefore, the PPT sequence may, in a gene therapy setting, be beneficial to prostate cancer patients that have been treated with androgen withdrawal [3].
• Therefore, we believe that an adenovirus with therapeutic gene expression controlled by an insulator-shielded PPT sequence is a promising candidate for gene therapy of prostate cancer [3].
• Preeclampsia and IUGR, often regarded to have the same pathological basis in common, showed distinct distributions of PP5/TFPI-2, which could be a clue to elucidate the pathogenesis of preeclampsia and IUGR [4].

Psychiatry related information on PPP5C

• These results suggest that PP5 plays a role in the dephosphorylation of tau and might be involved in the molecular pathogenesis of Alzheimer's disease [5].

High impact information on PPP5C

• Thus, CCRK and PP5 are yin-yang regulators of T157 phosphorylation [6].
• PP5 forms a complex with ATR in a genotoxic stress-inducible manner [7].
• In addition, loss of PP5 leads to premature mitosis after hydroxyurea treatment [7].
• In cells exposed to UV irradiation, PP5 is required to elicit an appropriate S-phase checkpoint response [7].
• Inhibition of PP5 activity did not activate HSF1 in unstressed cells [8].

Chemical compound and disease context of PPP5C

• A dehydrobutyrine (Dhb)-containing microcystin variant [Asp3, ADMAdda5, Dhb7]microcystin-HtyR isolated from Nostoc sp. was found to potently inhibit PP1, PP2A, PPP4 and PPP5 with IC50 values similar to those of microcystin-LR [9].

Biological context of PPP5C

• Down-regulation of PP5 activity by rapamycin coordinately activated ASK1, leading to elevated phosphorylation of c-Jun [10].
• Overexpression of PP5, but not the PP2A catalytic subunit, blocked rapamycin-induced phosphorylation of c-Jun, and protected cells from rapamycin-induced apoptosis [10].
• The findings suggest that in the absence of serum factors, mTOR signaling suppresses apoptosis through positive regulation of PP5 activity and suppression of cellular stress [10].
• Herein, we identify a Ser/Thr protein phosphatase (PP5) that promotes cellular proliferation by inhibiting both glucocorticoid and p53-mediated signaling pathways leading to p21(WAF1/Cip1)-mediated growth arrest [11].
• Serine/threonine protein phosphatase-5 (PP5) affects many signaling networks that regulate cell growth and cellular responses to stress [12].

Anatomical context of PPP5C

• In addition, indirect immunofluorescence showed that PP5 localizes to the mitotic spindle apparatus [13].
• Immunostaining demonstrated that PP5 was primarily cytoplasmic in PC12 cells and in neurons of postmortem human brain tissue [5].
• A small pool of PP5 associated with microtubules [5].
• Inhibition of PP2A, but not PP5, mediates p53 activation by low levels of okadaic acid in rat liver epithelial cells [14].
• To further characterize the role of PP5 in E(2)-regulated growth control, we constructed stable MCF-7 cell lines in which the expression of PP5 was placed under the control of tetracycline-regulated transactivator and operator plasmids [15].

Associations of PPP5C with chemical compounds

• Serine/threonine phosphatase 5 (PP5) can act as a suppresser of p53-dependent growth suppression and has been reported to associate with several proteins, including the glucocorticoid receptor/heat-shock protein-90 complex [16].
• PP5 is a serine/threonine phosphatase that also contains four copies of the tetratricopeptide repeats motif [13].
• Active forms of Galpha(12) and Galpha(13) also enhance the arachidonic acid-stimulated PP5 phosphatase activity about 2.5-fold [17].
• Only the NH2-terminal domain of PP5, containing all four tetratricopeptide repeats, is required for this physical interaction [13].
• Identification of an estrogen-inducible phosphatase (PP5) that converts MCF-7 human breast carcinoma cells into an estrogen-independent phenotype when expressed constitutively [15].

Physical interactions of PPP5C

• In Rh30 cells, ASK1 was found to physically interact with protein phosphatase 5 (PP5), previously identified as a negative regulator of ASK1 [10].
• Here we show by a combination of two-hybrid analysis and in vitro binding that PP5 interacts with CDC16 and CDC27, two subunits of the anaphase-promoting complex [13].
• The TPR domain of PP5 bound specifically to a 12-kDa C-terminal fragment of hsp90 [18].

Regulatory relationships of PPP5C

• Thus, aberrant PP5 expression may have an additive effect on the development of human cancers by promoting cell proliferation via the inhibition of a GR-induced antiproliferative signaling cascade, and facilitating neoplastic transformation via the inhibition of a growth-arresting p53-mediated response that guards against genomic instability [11].

Other interactions of PPP5C

• This allowed us to regulate the expression of either p53 (e.g. with ISIS 110332) or PP5 (e.g. with ISIS 15534) in genetically identical cells [16].
• First, in a rapid response hypoxia facilitates the association of endogenous PP5 with ASK-1 [1].
• Ser/Thr protein phosphatase type 5 (PP5) is a negative regulator of glucocorticoid receptor-mediated growth arrest [11].
• In this report, we demonstrate that protein phosphatase 5 (PP5) is required for the ATR-mediated checkpoint activation [7].
• Employing ISIS 15534, we demonstrate that the specific inhibition of PP5 gene expression has a marked antiproliferative effect on cells, characterized by induction of p21(WAF1/Cip1) and the subsequent arrest of cell growth [19].

Analytical, diagnostic and therapeutic context of PPP5C

• Conversely, microinjection of PP5 antibodies, or inhibition of its phosphatase activity in vivo, significantly delayed trimer disassembly after heat shock [8].
• Physical interactions between PP5 and HSF1-Hsp90 complexes were observed in co-immunoprecipitation and gel mobility supershift experiments [8].
• We have used site-directed mutagenesis to clarify the structural basis for the binding of hsp90 to the TPR domain of phosphoprotein phosphatase 5 (PP5) [18].
• RESULTS: To further characterize the mechanism by which PP5 affects GR-induced gene expression, we employed immunofluorescence microscopy to track the movement of a GR-green fluorescent fusion protein (GR-GFP) that retained hormone binding, nuclear translocation activity and specific DNA binding activity, but is incapable of transactivation [20].
• A recombinant adenovirus vector with the PPT sequence, shielded from interfering adenoviral sequences by the mouse H19 insulator, yields high and prostate-specific transgene expression both in cell cultures and when prostate cancer, PC-346C, tumors were grown orthotopically in nude mice [3].

References