Inhibition of cell proliferation by the interferon-inducible 204 gene, a member of the Ifi 200 cluster

Abstract

The role of the IFN-inducible p204 as growth regulator was investigated by transfecting an expression vector constitutively expressing p204 into several cell lines. Like pRB and p107, p204 is a potent growth inhibitor in sensitive cells, as demonstrated by the cell focus assay. Since stable transfectants of sensitive lines constitutively overexpressing p204 could not be established in vitro, we inserted the 204 cDNA into a vector bearing an heavymetal-inducible promoter. Here we show that proliferation of B6MEF ®broblasts lacking endogenous p204 is strongly inhibited by transient p204 expression in the nucleus. p204 delays G 1 progression into the S-phase and cells accumulate with a DNA content equivalent to cells arrested in late G 1 . Moreover, the role of p204 in the control of cell growth in vivo was investigated by generating transgenic mice in which the I® 204 gene was constitutively expressed in all tissues. To this end, expression vectors bearing the 204 cDNA under the control of the SV40 viral promoter were constructed. The overexpression of the p204 transgene achieved by injecting fertilized mouse eggs with these vectors was compatible with embryo development up to the four-cell stage in an in vitro follow-up of 4.5 days. However, no viable animals with an intact copy of the transgene were obtained, suggesting that high and constitutive levels of p204 expression can impair normal embryo development. These ®ndings indicate that p204 plays a negative role in growth regulation and provide new information about the molecular mechanisms exploited by IFNs to inhibit cell proliferation.

The interferon-inducible IFI16 gene inhibits tube morphogenesis and proliferation of primary, but not HPV16 E6/E7-immortalized human endothelial cells

“…Interestingly, the number of TO-IFI16-infected HUVEC did not vary significantly in the first 48 h when the levels of exogenous IFI16 are maximal, and started to double after 72 h along with the decrease of exogenous IFI16 expression. Moreover, the slope of the growth curve demonstrates that sustained and transient expression of exogenous IFI16 protein reversibly inhibits HUVEC proliferation without causing cell death in accord to the results obtained with Ifi204 overexpression in mouse fibroblasts [19,20]. These conclusions are further supported by the finding that IFI16-expressing HUVEC marginally undergo apoptosis as shown by annexin V binding (data not shown).…”

“…Overexpression of p204 in mouse embryo fibroblasts retarded their proliferation, delayed G1 progression into S-phase, and accumulated cells with a DNA content equivalent to cells arrested in late G1 [19]. These effects were strictly dependent on the association of progression with the Rb proteins [20,21].…”

The murine homolog of the HIN 200 family, Ifi 204, is constitutively expressed in myeloid cells and selectively induced in the monocyte/macrophage lineage

“…p204 is a 78-kDa phosphoprotein that increases several-fold on treatment with IFN-␣/␤ and then translocates into the nucleus [12]. On transfection in appropriate cell lines, both p202 and p204 slow down cell proliferation and accumulate cells at the G1/S border with a DNA content corresponding to 2N [13,14]. Taken as a whole, these results suggest that these two members control cell functions related to growth and differentiation.…”

p204 Protein Overcomes the Inhibition of Core Binding Factor α-1–mediated Osteogenic Differentiation by Id Helix-Loop-Helix Proteins

“…However, the antiproliferative activity of p204 does not always depend on pRb (Asefa et al, 2006) (Ding and Lengyel, unpublished data). Overexpression of p204 was found to delay the progression of cells from the G0/G1 phase to the S phase of the cell cycle (Lembo et al, 1998). p204 was found to be an important regulator of both skeletal and cardiac muscle differentiation (Liu et al, 2000(Liu et al, , 2002 Ding et al, 2006a,b).…”