Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IFI 16 is an interferon-inducible nucleoprotein expressed by human monocytes. IFI 16 and a related mouse protein, p202, control cellular proliferation by binding and modulating the functions of cell cycle regulatory factors including p53 and the retinoblastoma gene product, pRb. In this study, we examined IFI 16 expression in myeloid precursor cells cultured in vitro in colony-forming assays using granulocyte (G-) and granulocyte-macrophage (GM-) colony-stimulating factor (CSF). IFI 16 was expressed in 100% of CD34+ cells isolated from human bone marrow. When the CD34+ cells were induced to differentiate, two sub-populations of cells were identified by two-color cytofluorography: the CD14+ (monocytoid) cells all expressed IFI 16, whereas the CD14- (polymorphonuclear precursor) cells did not. The strongest expression of IFI 16 was in the cells staining brightest for CD14, whereas depletion of CD14+ monocytoid cells from mixed monocytic/granulocytic cultures largely abolished IFI 16-stained cells. Furthermore, in eight independent colony-forming assays, the number of IFI 16+ cells correlated closely with the numbers of monocyte precursors identified morphologically (R2 = 0.99), but was unrelated to the numbers of myelocytes, promyelocytes, and metamyelocytes; nor was IFI 16 expressed by erythroid or eosinophil precursors. We conclude that IFI 16 is expressed in CD34+ and monocytoid daughter cells, but is rapidly and markedly down-regulated at the corresponding stages of polymorphonuclear and erythroid development. This differential expression of IFI 16 in myeloid precursor subpopulations and its perceived molecular properties are consistent with a possible role in regulating myelopoiesis.
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PMID:The IFN-inducible nucleoprotein IFI 16 is expressed in cells of the monocyte lineage, but is rapidly and markedly down-regulated in other myeloid precursor populations. 976 36

Interferons are important in regulating cell growth and differentiation, immune function and initiating anti-viral responses. While the pleotrophic actions of interferons have been well documented, the molecular mechanisms underpinning their biological effects have not been fully characterized. IFI 16 is a member of the interferon-inducible HIN-200 family of nuclear proteins, which we have recently shown can function as a potent transcriptional repressor. A murine member of the HIN-200 family, p202, can indirectly interact with p53 via the p53 binding protein (p53bp) and inhibit p53-mediated transcriptional activation. The binding activity of p202 to p53bp was shown to require the conserved MFHATVAT motif present in all 200 amino acid repeat regions of HIN-200 proteins. Given that IFI 16 contains two MFHATVAT motifs, we sought to determine whether IFI 16 may form a complex with p53 and if so to ascertain the functional significance of this interaction. We demonstrate that IFI 16 can directly bind to the C-terminal region of p53 and augment p53-mediated transcriptional activation without altering the steady state levels of p53. Thus, in addition to its ability to directly regulate gene expression, IFI 16 can also modulate the transcription function of other cellular transcription factors. These findings demonstrate a possible link between gene induction following interferon stimulation and p53-mediated cellular events.
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PMID:Functional interaction between p53 and the interferon-inducible nucleoprotein IFI 16. 1114 55

Defects in interferon (IFN) signaling that result in loss of expression of IFN-inducible proteins are associated with cellular immortalization, an important early event in the development of human cancer. Here we report that loss of IFN-inducible IFI 16 expression in human fibroblasts allows bypass of cellular senescence. We found that levels of IFI 16 mRNA and protein were higher in human old versus young fibroblasts and immortalization of fibroblasts with telomerase resulted in decreased expression of IFI 16. Moreover, overexpression of IFI 16 in immortalized fibroblasts strongly inhibited cell proliferation. Interestingly, knockdown of IFI 16 expression in fibroblasts inhibited p53-mediated transcription, downregulated p21(WAF1) expression, and extended the proliferation potential. Importantly, treatment of immortal cell lines with 5-aza-2'-deoxycytidine, an inhibitor of DNA methyltransferase, resulted in upregulation of IFI 16. Our observations support the idea that increased levels of IFI 16 in older populations of human fibroblasts contribute to cellular senescence.
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PMID:Role of IFI 16 in cellular senescence of human fibroblasts. 1520 61

Expression of the human HIN-200 family member IFI 16 has been reported to suppress cell growth and contribute to the onset of cellular senescence. However the molecular events involved in this process have not been fully characterised. We fused IFI 16 to the estrogen receptor ligand-binding domain to establish an inducible model for studying the molecular events that cause these phenomena. In cells induced to express the ER-IFI 16 within the nucleus there was a decrease in cellular proliferation and concomitant growth arrest in the G1 phase of the cell cycle. Unlike previous reports, this did not appear to involve the p53-p21(WAF1/CIP1)-cdk2-pRb pathway. Following nuclear expression of ER-IFI 16 we noted senescence-like morphological changes and expression of senescence-associated beta-galactosidase in growth arrested cells. Importantly, we also found a marked reduction in telomerase activity in arrested cells compared to controls. Moreover, IFI 16 and hTERT co-localised within the nucleus and these two proteins physically interacted in vivo and in vitro. Together, these data suggest that IFI 16 may act as an endogenous regulator of telomerase activity and, through its interaction with hTERT, contributes to the inhibition of proliferation and induces a senescence-like state.
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PMID:Inducible activation of IFI 16 results in suppression of telomerase activity, growth suppression and induction of cellular senescence. 1988 68