Disease relevance of IFI27

• To further characterize its function, we studied by in situ hybridization whether IFI27 is expressed in psoriasis, other inflammatory skin diseases, and wound repair in vivo [1].
• It was also expressed in lichen planus, chronic eczema, cutaneous squamous cell cancers, and during normal wound repair when IFI27 was found in the proliferating subpopulation of keratinocytes [1].
• In comparison with idiopathic thrombocytopenic purpura (ITP), an organ-specific autoimmune disease, IFI27, G1P2 and SLED1 were preferentially upregulated in SLE [2].
• These data demonstrate that depletion of either p21 or p27 can mimic estrogen-stimulated cell cycle activation and indicate that both of these KIPs are critical mediators of the therapeutic effects of antiestrogens in breast cancer [3].
• High levels of p27 RNA were found in vivo in approximately 50% of primary human breast carcinomas (21 were tested by Northern blotting) [4].

Psychiatry related information on IFI27

• Increased p27, an essential component of cell cycle control, in Alzheimer's disease [5].
• Sensory neglect and apomorphine-induced rotation were measured at P27 and P28 [6].

High impact information on IFI27

• In this issue, two papers () address this problem by reporting phosphorylation of the cyclin-dependent kinase inhibitor p27(Kip1) on a tyrosine residue by nonreceptor tyrosine kinases, which decreases p27 stability [7].
• Y88 phosphorylation does not prevent p27 binding to cyclin A/Cdk2 [8].
• This direct link between transforming tyrosine kinases and p27 may provide an explanation for Cdk kinase activities observed in p27 complexes and for premature p27 elimination in cells that have been transformed by activated tyrosine kinases [8].
• A conserved tyrosine residue (Y88) in the Cdk-binding domain of p27 can be phosphorylated by the Src-family kinase Lyn and the oncogene product BCR-ABL [8].
• Instead, it causes phosphorylated Y88 and the entire inhibitory 3(10)-helix of p27 to be ejected from the Cdk2 active site, thus restoring partial Cdk activity [8].

Chemical compound and disease context of IFI27

• ErbB2 or ErbB1 overexpression can abrogate tamoxifen sensitivity in breast cancer lines through both reduction in p27 levels and inhibition of its function [9].
• These findings suggested that p21, p27, and p18 might be involved in troglitazone-induced cell-cycle arrest in human hepatoma cells [10].
• Protein levels of p21, p27, cyclin E and Bax predict sensitivity to cisplatin and paclitaxel in head and neck squamous cell carcinomas [11].
• 1,25(OH)2 vitamin D3 induces elevated expression of the cell cycle-regulating genes P21 and P27 in squamous carcinoma cell lines of the head and neck [12].
• Our findings highlight p27 and VD analogs as targets for manipulation and drug development respectively in the treatment of inoperable corticotroph adenomas [13].

Biological context of IFI27

• In addition, these results suggest that there is a link between p27 expression and the ability of CLL cells to undergo apoptosis [14].
• The relation of TGF-beta 1 stimulation to p21 and p27 was examined using a fine-mapping approach to gene expression in individual cells [15].
• Although multiple factors influence pRb phosphorylation, it appears that both cyclin D1 and p21 expression do not change in the presence of DHA, although p27 was strikingly increased in SK-Mel-110 cells in the absence of FBS [16].
• The involvement of p27 in the negative regulation of cell proliferation suggests that it may also function as a tumor suppressor gene [17].
• Identification of a new interferon-alpha-inducible gene (p27) on human chromosome 14q32 and its expression in breast carcinoma [4].

Anatomical context of IFI27

• IFI27 mRNA expression was highly upregulated in lesional psoriatic epidermis and also detected in non-lesional keratinocytes [1].
• In contrast to the widespread expression of p21 and p27 in human tissues, p57 is expressed in a tissue-specific manner, as a 1.5-kb species in placenta and at lower levels in various other tissues and a 7-kb mRNA species observed in skeletal muscle and heart [18].
• In B-CLL, p27 levels were independent of absolute number of circulating lymphocytes, but strongly correlated with both lymphocyte and total tumor mass (TTM) doubling time [14].
• Investigations in a human mammary epithelial cell (HMEC) model, including cells that are sensitive (184(S)) and resistant (184A1L5(R)) to G(1) arrest by TGF-beta, revealed aberrant p27 regulation in the resistant cells [19].
• Skp2 is required for endothelial cell proliferation as a consequence of degrading p27 [20].

Associations of IFI27 with chemical compounds

• Tamoxifen activates the cyclin-dependent kinase inhibitor, p27 to mediate G(1) arrest [9].
• A new complementary DNA, p27, has been cloned and sequenced from estradiol-treated MCF7 human breast carcinoma cells [4].
• Apigenin inhibits endothelial-cell proliferation in G(2)/M phase whereas it stimulates smooth-muscle cells by inhibiting P21 and P27 expression [21].
• On the other hand, Northern blotting showed that artepillin C did not affect the expression of Kip1/p27 mRNA [22].
• While p27 was increased by monensin, p21 was not [23].

Physical interactions of IFI27

• Despite a reduction in total and cyclin E-Cdk2 bound p27 after ASp27 transfection, HMECs remained arrested in the G(1) phase [24].
• Here we show that Bcr-Abl tyrosine kinase facilitates the down-regulation of p27 by modulating complex formation of Jab1/CSN through the mitogen-activated protein (MAP) kinase and phosphatidylinositol 3 (PI3) kinase signaling pathways [25].
• Finally, binding of Max was shown to facilitate c-Myc binding and repression of p27 promoter activity [26].
• The degradation of Skp2 stabilizes p27, thereby ensuring TGF-beta-induced cell cycle arrest [27].
• We report here that Skp2 is rapidly degraded following cellular stimulation by the cytokine transforming growth factor beta (TGF-beta) and that this degradation stabilizes the cell cycle arrest protein p27 [27].

Enzymatic interactions of IFI27

• Transduction of BT-474 cells with an adenovirus-encoding active (myristoylated) Akt (Myr-Akt), but not with a beta-galactosidase control adenovirus, prevented the Herceptin- or LY294002-induced down-regulation of cyclin D1 and of phosphorylated GSK-3beta and prevented the accumulation of p27 in the nucleus and cytosol [28].

Regulatory relationships of IFI27

• TGF-beta1 treatment induced P27 to congregate around nucleus [29].
• Cyclin-dependent protein kinase activities were downregulated and p27, the cyclin-dependent kinase inhibitor, was activated by GST-D5 [30].
• In Mv1Lu cells containing a p27 inducible system, a 6-fold increase over the basal p27 level completely inhibited Cdk2 and cell cycle progression [31].
• p27kip1 is a cyclin-dependent kinase inhibitor which controls the G1 phase of the cell cycle in conjunction with pRb. p27 has been associated with cell-cycle arrest and apoptosis [32].
• Stimulation with TPO or IL-3 induced a rapid decrease of p27 mRNA [33].

Other interactions of IFI27

• In bone marrow, p21 was immunostained almost exclusively in a subset of megakaryocytes and p27 protein was present in megakaryocytes, plasma cells, and endothelial cells [34].
• In contrast to the findings in HMECs, p27 was essential for G(1) arrest by TGF-beta in two tumor-derived lines [24].
• The decrease in cdk2 activity occurred in the absence of RA-mediated increases in the levels of the cdk inhibitors p21 and p27 [35].
• Proteasome-dependent degradation of p27/kip1 in gliomas [36].
• Examination of cyclins D and E, p53, Rb, and p27 revealed a largely nonproliferative expression profile [37].

Analytical, diagnostic and therapeutic context of IFI27

• The expression of cell cycle-regulating proteins, such as p21, p27, p18(INK4c), cyclin E, and pRb, was examined using Western blotting [10].
• In univariate analysis, cases with p27 LI < 50 (P =.0004), cyclin D1 overexpression (P =.0041), and cyclin E overexpression (P =.0572, borderline significance) showed poorer outcomes for disease-free survival (DFS) [38].
• We assessed p27 and p53 expressions by immunohistochemistry [39].
• Among these, an interferon-induced gene, IFI27, was differentially expressed among all three types of HCCs, and this result was confirmed by RT-PCR [40].
• Two homozygous deletions of the p27 gene were detected in one case of B-immunoblastic NHL and in one case of acute ATL by Southern blot hybridization [41].

References