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Department of Oncology, Sidney Kimmel Comprehensive Cancer Center [B. J. B., M. J. K., K. E. P., J. A. F., P. M. P.] and Department of Molecular Biology and Genetics [P. M. P.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Studies on the IRF family members have revealed that many are involved in the regulation of cell growth, differentiation, and oncogenesis (6, 7, 8, 9, 10, 11) . The precise mechanisms underlying IRF-mediated tumor suppression and oncogenesis remain to be elucidated. IRF-1, IRF-3, and IRF-8 (IFN consensus sequence binding protein) have been shown to function as tumor suppressor proteins and/or mediators of virus-induced apoptosis by activating a set of target genes that could induce tumor suppression such as those responsible for the inhibition of cell growth, induction of apoptosis, and possibly regulation of DNA repair (6, 7, 8, 9, 10 , 12 , 13) .
In an effort to gain additional insight into the possible role of IRF-5 in oncogenesis, we have analyzed the effect of IRF-5 on cell cycle, tumor growth, and apoptosis. We have found that IRF-5 inhibits the growth of tumor cells both in vitro and in vivo, thus indicating that IRF-5 has tumor suppressor properties. Focusing on the molecular mechanism of this inhibition, we show that IRF-5 induces G2-M cell cycle arrest, induction of Bak, caspase 8, Bax, and p21 genes, along with multiple cell cycle regulatory and proapoptotic genes. These studies additionally reveal that although wt p53 stimulates expression of IRF-5, the proapoptotic and cell cycle regulatory effects of IRF-5 are completely independent of p53. In addition, we show that expression of IRF-5 is suppressed in a number of primary hematological malignancies, suggesting a possible role for IRF-5 in lymphomagenesis. Taken together, these data indicate that although IRF-5 is a downstream component of the p53-signaling pathway, its function is independent of p53.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Antibodies.
The M2 anti-Flag antibodies were obtained from Sigma (St. Louis, MO); polyclonal anti-IRF-5 antibodies were obtained from Abcam (Cambridge, United Kingdom); monoclonal anti-p21 (OP64), anti-p53 (OP33), anti-p53 (OP43), anti-bak1 (AM03), anti-caspase 8 (AM46), polyclonal anti-bax (PC66), and anti-cyclin B (PC133) antibodies were from Oncogene (Cambridge, MA); polyclonal anti-DAP kinase 2 (251710) antibodies were from Calbiochem (San Diego, CA); monoclonal anti-CD95 antibodies were from BD PharMingen (San Diego, CA).
FACS Analysis and Immunofluorescence.
BJAB or HCT116 p53-/- cells (5 x 105) were stained with Hoechst 33258 (Sigma) dye (18)
and analyzed by flow cytometry for determination of cell cycle and by fluorescent microscopy for cell morphology. Apoptosis was quantified by single PI (BD PharMingen, Lexington, KY) and/or Hoechst 33258 staining and Annexin-FITC-PI (BD PharMingen) double staining according to standard procedures given by the manufacturers on a Becton Dickinson LSR flow cytometer (San Jose, CA). BJAB cells were incubated with anti-CD95 antibodies for 8–10 h and then stained with Annexin-FITC and PI and analyzed by FACS.
Colony Formation Assay and Animal Studies.
BJAB cell lines were plated in duplicate with serial dilutions of 105 to 103 cells/ml in 0.35% agar-media. Colony formation was evaluated after 14–28 days by staining the cells with crystal violet. Female athymic NCr-nude mice (NCI, Frederick, MD), 6–8 weeks old, were injected s.c. with 5 x 106 viable BJAB vector control cells, BJAB/IRF-5 cells, or BJAB/IRF-7 cells. Tumor cell growth was monitored over a 6-week period when tumor size of BJAB-injected control mice reached 
15 mm. Tumor size and validity were assessed after sacrificing mice, excising tumor nodules for measurement, and RNA isolation.
DNA Microarray Analysis.
Total RNA was isolated from BJAB vector control cells and BJAB/IRF-5-expressing cells and transcribed to cDNA. P32-labeled DNA probes were generated and hybridized to the human apoptosis, p53 signaling, and/or cell cycle pathway GEArray Q series microarrays (SuperArray, Inc., Bethesda, MD) that each contained a total of 96 key genes involved with apoptosis or cell cycle regulation. The hybridization data were analyzed using the Image analysis software (Scanalyze by Michael Eisen) and the GEArrayAnalyzer v.1.2.31 (SuperArray, Inc.).
RT-PCR Analysis and RPA.
BJAB or HCT116 cells were treated with 0.2 µg/ml Adriamycin for 16 h or 500 units/ml IFN-
for 16 h. Total RNA was reverse transcribed to cDNA using oligo(dT) primers. From this mixture of cDNAs, IRF-3, IRF-5, IRF-7, and ß-actin were amplified by semiquantitative PCR under conditions that give a linear response, as described previously (1
, 2)
. p21 was amplified with the following primers: sense, 5'-CCTCTTCGGCCCGGTGGAC-3'; antisense, 5'-CCGTTTTCGACCCTGAGAG-3'. Total RNA was also analyzed by the RPA as previously described (2)
using the hAPO-1c, hAPO-2b, or hStress-1 multiprobe template sets (BD PharMingen).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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reveals that although low levels of endogenous IRF-5 could be detected in both the untreated and Adriamycin-treated p53-/- cells, Adriamycin stimulated expression of IRF-5 (4-fold) and p53 in p53+/+ cells. However, Adriamycin did not induce IRF-5 in p53-/- cells. In addition, treatment of cells with Irinotecan, another inducer of p53, stimulated expression of both IRF-5 and p21 genes. Under the same conditions, the levels of IRF-3 transcripts were unaffected by Irinotecan in these cells.4
These results indicate that expression of IRF-5 is enhanced by Adriamycin- or Irinotecan-induced p53.
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, treatment of these cells with IFN- significantly increased the levels of IRF-5 and p21 transcripts, as well as the percentage of HCT116 p53-/- cells arrested in G2-M (Fig. 1D)
. Cotransfection of an IRF-5 expression plasmid with a p21 luciferase reporter in Saos cells (p53-/-) resulted in a 7-fold increase in the transactivation of the p21 promoter (Fig. 1C)
. Transfection of an IRF-5-expressing plasmid to HCT116 p53-/- cells resulted in a substantially more effective G2-M cell arrest than by IFN treatment alone (Fig. 1D)
. The levels of IRF-5 protein expressed in transfected cells were 2.5-fold higher than the levels induced by IFN (Fig. 1E)
. These data indicate that the G2-M cell arrest is related to the levels of IRF-5 expressed in the cells. Furthermore, although p53 induced IRF-5 expression, overexpression of IRF-5 alone in the absence of wt p53 was sufficient to trigger cell cycle arrest. These data also suggest that IRF-5 may be one of the factors that plays a role in IFN-mediated cell growth inhibition (20, 21, 22, 23)
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IRF-5-induced G2-M Arrest and Apoptosis Is Independent of p53.
We next used the human BJAB B-cell lymphoma line to examine closely the function of IRF-5 in cell growth regulation. As shown in Fig. 2A
, although BJAB cells expressed nearly undetectable levels of constitutive IRF-5 transcripts, expression of IRF-3 and IRF-7 could be readily detected. Treatment of BJAB cells with IFN (Fig. 2A
, Lane 3) revealed that expression of IRF-5 could be stimulated (Fig. 2A)
. As shown in Fig. 2, B and C
, although BJAB cells express high levels of p53, the fact that Adriamycin did not stimulate expression of p53 or p21 indicates that BJAB cells express mutant nonfunctional p53 (16)
. As a control, we show that Adriamycin induces p53 expression in p53+/+ cells and not in p53-/- cells. Furthermore, by immunoblot analysis using monoclonal antibodies recognizing both a mutant and wt p53 (OP43) or wt p53 alone (OP33), wt p53 was detected only in lysates from p53+/+ cells and not in BJAB cells (Fig. 2C)
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. Furthermore, Irinotecan (p53 inducer) enhanced the IFN-mediated expression of IRF-5 (from 2- to 5-fold induction) in p53+/+ cells but not in p53-/- cells (3)
. These results indicate that p53 and IFN-mediated induction of IRF-5 is synergistic.
On the basis of these findings, we constructed BJAB B-lymphoma clonal lines overexpressing Flag-tagged IRF-5. For comparison, we also generated BJAB cells overexpressing Flag-tagged IRF-7 (Fig. 2E)
. During passage of these cells in culture, we noticed a continuous reduction (10–30%) in the growth rate of IRF-5-expressing cells as compared with BJAB control cells over a 48–72-h time period, as determined by the number of viable cells. Whereas the growth rate of IRF-7-expressing BJAB cells and vector control cells did not change (data not shown). To examine the effect of ectopic IRF-5 or IRF-7 expression on cell cycle progression, cells were stained with Hoechst 33258, and the G1-gated population of viable cells was examined by FACS. Although the majority (45–50%) of BJAB cells transfected with empty vector or IRF-7-expressing plasmid were in the G1 phase of the cell cycle (fraction of cells represented as M1), BJAB/IRF-5-expressing cells revealed an explicit G2-M arrest (fraction of cells represented as M2; Fig. 2F
). When BJAB vector control cells and BJAB/IRF-5-expressing cells were stained with Hoechst 33258 and examined by fluorescent microscopy, there was a distinct morphological difference between the BJAB control cells and BJAB/IRF-5 cells. Interestingly, IRF-5-expressing cells, but not control cells, showed the presence of apoptotic cell bodies (30%), as determined in the sub-G0-G1 fraction (PI positive) of ungated IRF-5-expressing cells by FACS analysis (data not shown).
To further confirm these findings, Annexin-FITC and PI-labeled BJAB cells and BJAB/IRF-5-expressing cells were analyzed by FACS. In BJAB cells, only 1.4% of the population stained positive for FITC and PI (Fig. 2G)
. Treatment of these cells with anti-CD95 antibody for 6 h induced apoptosis, and 32% of the cells were positive for FITC and 13% for FITC and PI, indicating induction off early-to-late stages of apoptosis. Analysis of BJAB/IRF-5-expressing cells have shown that 31% of the population was stained positive for both FITC and PI and 60% for FITC alone. Thus, similar to the treatment of BJAB cells with anti-CD95 antibodies, overexpression of IRF-5-induced apoptosis in BJAB cells.
Overexpression of IRF-5 but not IRF-7 Inhibits Growth of BJAB Tumor Cells in Soft Agar and in Vivo.
BJAB cells originated from a B-cell lymphoma that can form colonies in soft agar and tumors in nude mice. We therefore examined the effect of IRF-5 and IRF-7 on the ability of BJAB cells to form colonies in soft agar. As shown in Fig. 3A
, BJAB/IRF-5 c.14 was unable to grow in soft agar although both BJAB/IRF-7 c.2 and BJAB control cells formed colonies efficiently. The inhibition of colony formation was related to the level of IRF-5 expression because c.14 (a high expressor) was unable to grow, whereas c.3 (a low expressor; Fig. 2E
, Lane 2) was able to grow in soft agar, although with lower efficiency than BJAB control cells (Fig. 3A)
. The number of colonies was reduced by 70–80% as compared with BJAB control colony formation.
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15 mm. Although multiple tumors were detected in group 1, only single tumors were detected in group 2. However, both groups 1 and 2 had formed tumors as early as 3 weeks after injection, and tumors ranged in size from 15 to 20 mm after a 6-week incubation period. Group 3 did not show any tumor growth by external visual inspection (Fig. 3B)
. However, upon internal inspection, three of the six mice in group 3 had very small tumors (<5 mm in size). To determine whether tumors obtained from groups 2 and 3 still expressed the human IRF-7 or IRF-5, respectively, RNA isolated from these tumors was analyzed by RT-PCR. The analysis revealed that two of three tumors excised from mice in group 3 lost expression of IRF-5, whereas all tumors from group 2 mice expressed high levels of IRF-7 (data not shown). These results indicate that IRF-5 was a substantially more effective inhibitor of tumor growth than IRF-7 because IRF-7-expressing tumors were still present in each mouse. Furthermore, IRF-7 expression did not result in the modulation of cell cycle or growth of BJAB cells in soft agar, whereas IRF-5-expressing cells were arrested at G2-M and unable to grow as tumors.
IRF-5 Targets Genes Regulating Cell Cycle and Apoptosis.
To elucidate the molecular mechanism by which IRF-5 induces cell arrest and cell death, we examined the potential impact of IRF-5 expression on the transcription of cellular genes associated with cell cycle regulation and apoptosis. To this effect, we used RNA from BJAB, BJAB/IRF-5, HCT116 p53-/-, and HCT116 p53-/-/IRF-5-expressing cells and examined gene expression using the human apoptosis, p53 signaling, and cell cycle-specific cDNA microarrays. Table 1
shows a group of selected genes that were regulated by at least 2.5-fold in the presence of IRF-5 and the absence of wt p53. Although a number of the IRF-5-regulated genes such as p21, Bax, caspase 6, B99, and Bcl-2 represent a subset of known p53 target genes, a large group of unique genes (18 of 24 regulated genes) such as Bak1, caspase 8 and Dap-kinase 2 were up-regulated by IRF-5 alone (Table 1)
. On the other hand, a number of p53 target genes, including PUMA, 14-3-3, and Bcl-x were not targeted by IRF-5 (data not shown). These results suggest that although there is some overlap in gene regulation by IRF-5 and p53, the pathways emanating from these two factors are not redundant.
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. Fig. 4A
reveals that each of the analyzed gene transcripts predicted by microarray to be modulated by IRF-5 were indeed up-regulated or down-regulated by the RPA. Finally, by immunoblot analysis, we show that the IRF-5-mediated modulation of gene transcription also results in an alteration of the relative levels of respective proteins (Fig. 4B)
. Taken together, these results indicate that IRF-5-induced gene regulation is direct and independent of wt p53 and places IRF-5 downstream of p53 (Fig. 4C)
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, a number of the IRF-5 target genes contained IRF-E sites indicating that IRF-5 may be able to bind to the promoter and participate in the transcriptional regulation of these genes. By transient cotransfection assay, IRF-5 indeed stimulated the transcriptional activity of the p21 promoter in Saos (p53-/-) cells, indicating that the IRF-E in the p21 promoter is recognized by IRF-5 and activation of the p21 promoter does not require p53 (Fig. 1C)
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IRF-5 Gene Expression Is Lacking in a Large Number of Primary Hematological Malignancies.
By Northern blot analysis, we have previously shown that the constitutive expression of IRF-5 occurs primarily in lymphoid tissue, peripheral blood lymphocytes, and dendritic cells yet was not detected in a number of immortalized B- and T-cell leukemias (1)
. Here, we have additionally extended and confirmed these findings by comparing IRF-5 expression levels in mononuclear cells from healthy donors or from patients with CLL, ALL, or AML. For comparison, we have examined expression of the IRF-7 gene because it is also expressed primarily in lymphoid tissue (25)
. Furthermore, expression of the IRF-7 gene was found to be silenced by hypermethylation in some tumor cell lines (26)
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Expression of IRF-5 and IRF-7 was detected in mononuclear cells from all healthy donors (Fig. 5
, Lanes 1–6). We also detected constitutive expression of IRF-5 and IRF-7 in purified human activated monocytes and B- or T cells by intracellular flow, indicating that IRF-5 expression is not down-regulated in activated cells.5
, 6
In contrast, IRF-5 mRNA was not detected in the majority of leukemia cells from patients with hematological malignancies (Fig. 5)
. The most striking defect in IRF-5 expression was seen in patients with ALL where none of the 10 examined primary tumors expressed IRF-5 (Fig. 5
, Lanes 7–12). However, IRF-7 was expressed in all of the tumors examined although the relative levels of expression have shown large variability. These data indicate that the silencing of IRF-5 expression in hematological malignancies may be associated with leukemogenesis.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The tumor suppressing activity of IRF-5 was further demonstrated in BJAB B-cell lymphoma, where ectopic expression of IRF-5 induced a G2-M arrest, inhibited cell growth in soft agar, and tumor formation in nude mice. While addressing the molecular nature of this inhibition, our studies revealed that IRF-5 stimulates expression of the cyclin-dependent kinase inhibitor p21cip1/waf1 and represses cyclin B1, both of which are responsible in part for the regulation of a G1-S and/or G2-M cell cycle checkpoint. In addition, IRF-5 stimulates expression of several proapoptotic genes such as Bak1, Bax, caspase 8, and DAP kinase-2. The ability of IRF-5 to induce cell arrest and cell death is also one of the multifaceted activities of p53; yet, our data indicate that IRF-5 and p53 induce both a set of overlapping and distinct genes. As shown in this study, the IRF-5-mediated growth inhibition and proapoptotic effects are p53 independent. These results and previous data (2)
suggest that IRF-5 functions as an intermediate in the information cascade initiating from p53 or IFN to effector genes that either induce a program of cell arrest, cell death, or immunomodulation (Fig. 4C)
.
The critical role of p21 and cyclin B1 in growth arrest has been well established (14 , 16 , 27 , 28) . Although most of the studies on p21-regulated checkpoints have been focused on the G1-S transition, several previous observations point to the importance of this gene in G2-M (14 , 27 , 29, 30, 31, 32) . For instance, tumor cells lacking functional p21 were shown to be defective in the control mechanism at the G2-M checkpoint and thus proceed through multiple rounds of S phase (33) . Furthermore, B99, BRCA1, and Chk1/Chk2 expression, which was also stimulated by IRF-5, play an important role in G2-M cell arrest (34, 35, 36, 37, 38, 39) . Thus, results reported herein implicate IRF-5 as a trigger for cell cycle arrest within the G2 phase. Available evidence, thus far, would suggest that this is achieved, at least in part, by IRF-5-induced expression of p21. However, additional studies are necessary to determine the contribution of p21 and other growth regulatory genes induced by IRF-5 to the observed cell cycle arrest.
The ability of IRF-5 to induce expression of proteins involved in cell growth regulation and immunomodulation represents an important defense mechanism against extracellular stress, including viral infection. We have performed detailed microarray studies to examine more closely the genes regulated by IRF-5. Preliminary results indicate that in addition to cell cycle regulatory and proapoptotic genes, IRF-5 induces a large number of immune response genes, IFN-induced proteins, and ubiquitin enzymes (data not shown). Interestingly, a number of these IRF-5 target genes were induced in both p53-/- and p53+/+ cells, indicating the importance of IRF-5 in p53-dependent immune response (data not shown). Viral oncoproteins encoded by many DNA tumor viruses are able to bind p53. The adenovirus-encoded E1A protein induces a rapid p53-dependent apoptotic response, whereas the E1B protein binds p53 and inhibits its function (40 , 41) . Human cytomegalovirus major IE proteins (42) , EBV nuclear antigen (43) and hepatitis B virus X protein (44) , all form complexes with the p53 protein and inhibit its transactivation function. Lastly, the human papillomavirus E6 protein induces the degradation of p53 (45) . Thus, all of these viruses developed mechanisms by which they can override the host response against infection. In a similar manner, many viruses encode proteins that target IRF function and the antiviral response (46, 47, 48, 49) . Taken together, these data indicate that both p53 and IRF have important roles in host response to viral infection.
The role of two IRF family members in the induction of apoptosis has been well established. IRF-1-targeted genes include p21, caspase 1, and lysyl oxidase genes (12 , 50 , 51) , and IRF-3 mediates Sendai-virus-induced apoptosis through stimulation of caspases 8 and 3 (7) . In this study, we show that IRF-5 modulates the expression of a number of factors involved in cell cycle regulation and apoptosis, independent of viral infection. Additional studies are necessary to determine the exact position IRF-5 holds in the apoptotic signaling pathway. The observation that some of the growth regulatory and proapoptotic functions of p53 can be replaced by IRF-5 suggests that a closer analysis of pathways leading to and from IRF-5 may provide novel strategies for cell growth management. Clinically, the loss of p53 function is associated with resistance to apoptosis and treatment failure. By demonstrating the proapoptotic and antitumor activity of IRF-5 in the absence of functional p53, our data suggests that induction of IRF-5 expression may lead to novel therapeutic strategies for treatment of cancers deficient in p53 function. Furthermore, the induction of IRF-5 expression may increase the sensitivity of p53-deficient tumors to drug-induced apoptosis. We are currently exploring both of these possibilities.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by NIH National Institute of Allergy and Infectious Diseases Grant R01AI-19737-19 and R21AI19737-19 (to P. M. P.), an Anti-Cancer Drug Development Pharmacology-Oncology training grant, and American Cancer Society Grant IRG-58-005-41 (to B. J. B.). 
2 To whom requests for reprints should be addressed, at The Johns Hopkins University, Oncology Center, 1650 Orleans Street, Baltimore, MD 21231. Phone: (443) 287-2758; Fax: (410) 955-0840; E-mail: barnebe{at}jhmi.edu
3 The abbreviations used are: IRF, IFN regulatory factor; wt, wild type; CLL, chronic lymphocytic leukemia; ALL, acute lymphocytic leukemia; AML, acute monocytic leukemia; FACS, fluorescence-activated cell sorting; PI, propidium iodide; RT-PCR, reverse transcription-PCR; RPA, RNase protection assay.
4 B. J. Barnes and R. Ravi, unpublished data.
5 A. Izaguirre, B. J. Barnes, S. Amrute, W. S. Yeow, N. Megjugorac, J. Dai, D. Feng, E. Chung, P. M. Pitha, and P. A. Fitzgerald-Bocarsly. Comparative analysis of IRF and IFN- expression in human plasmacytoid and monocyte derived dendritic cells. J. Leuk. Biol., in press, 2003.
6 S. Amrute and B. J. Barnes, unpublished data.
Received 3/10/03. Revised 6/17/03. Accepted 7/24/03.
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C. M. Bailey, Z. Khalkhali-Ellis, S. Kondo, N. V. Margaryan, R. E. B. Seftor, W. W. Wheaton, S. Amir, M. R. Pins, B. C. Schutte, and M. J. C. Hendrix Mammary Serine Protease Inhibitor (Maspin) Binds Directly to Interferon Regulatory Factor 6: IDENTIFICATION OF A NOVEL SERPIN PARTNERSHIP J. Biol. Chem., October 7, 2005; 280(40): 34210 - 34217. [Abstract] [Full Text] [PDF]
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G. Hu, M. E. Mancl, and B. J. Barnes Signaling through IFN Regulatory Factor-5 Sensitizes p53-Deficient Tumors to DNA Damage-Induced Apoptosis and Cell Death Cancer Res., August 15, 2005; 65(16): 7403 - 7412. [Abstract] [Full Text] [PDF]
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E. Turpin, K. Luke, J. Jones, T. Tumpey, K. Konan, and S. Schultz-Cherry Influenza Virus Infection Increases p53 Activity: Role of p53 in Cell Death and Viral Replication J. Virol., July 15, 2005; 79(14): 8802 - 8811. [Abstract] [Full Text] [PDF]
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M. E. Mancl, G. Hu, N. Sangster-Guity, S. L. Olshalsky, K. Hoops, P. Fitzgerald-Bocarsly, P. M. Pitha, K. Pinder, and B. J. Barnes Two Discrete Promoters Regulate the Alternatively Spliced Human Interferon Regulatory Factor-5 Isoforms: MULTIPLE ISOFORMS WITH DISTINCT CELL TYPE-SPECIFIC EXPRESSION, LOCALIZATION, REGULATION, AND FUNCTION J. Biol. Chem., June 3, 2005; 280(22): 21078 - 21090. [Abstract] [Full Text] [PDF]
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S. Ning, L. E. Huye, and J. S. Pagano Regulation of the Transcriptional Activity of the IRF7 Promoter by a Pathway Independent of Interferon Signaling J. Biol. Chem., April 1, 2005; 280(13): 12262 - 12270. [Abstract] [Full Text] [PDF]
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H. Chen, J. Huang, F. Y. Wu, G. Liao, L. Hutt-Fletcher, and S. D. Hayward Regulation of Expression of the Epstein-Barr Virus BamHI-A Rightward Transcripts J. Virol., February 1, 2005; 79(3): 1724 - 1733. [Abstract] [Full Text] [PDF]
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R. Lin, L. Yang, M. Arguello, C. Penafuerte, and J. Hiscott A CRM1-dependent Nuclear Export Pathway Is Involved in the Regulation of IRF-5 Subcellular Localization J. Biol. Chem., January 28, 2005; 280(4): 3088 - 3095. [Abstract] [Full Text] [PDF]
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B. J. Barnes, J. Richards, M. Mancl, S. Hanash, L. Beretta, and P. M. Pitha Global and Distinct Targets of IRF-5 and IRF-7 during Innate Response to Viral Infection J. Biol. Chem., October 22, 2004; 279(43): 45194 - 45207. [Abstract] [Full Text] [PDF]
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2.5–4.99-fold induction; (++) 
0.0. The data are representative of two to three independent microarray gene array experiments. The number(s) of IRF-E consensus sequence(s) in the promoter is indicated, except in those cases where sequences have not been deposited in GenBank (NA, not available).
