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Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, Vol. 94 No. 9 (November 1), 1999: pp. 3129-3134 Overexpression of I Kappa B Alpha Without Inhibition of NF-B Activity and Mutations in the I Kappa B Alpha Gene in Reed-Sternberg Cells By Florian Emmerich, Martina Meiser, Michael Hummel, Gudrun Demel, Hans-Dieter Foss, Franziska Jundt, Stephan Mathas, Daniel Krappmann, Claus Scheidereit, Harald Stein, and Bernd Dörken From Humboldt University of Berlin, Universitätsklinikum Charité, Robert-Rössle-Klinik, Berlin; the Max Delbrück Center for Molecular Medicine, Berlin; and the Institut for Pathology, Universitätsklinikum Benjamin Franklin, Free University Berlin, Berlin, Germany.     ABSTRACT TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES The transcription factor NF kappa B (NF-B) mediates the expression of numerous genes involved in diverse functions such as inflammation, immune response, apoptosis, and cell proliferation. We recently identified constitutive activation of NF-B (p50/p65) as a common feature of Hodgkin/Reed-Sternberg (HRS) cells preventing these cells from undergoing apoptosis and triggering proliferation. To examine possible alterations in the NF-B/IB system, which might be responsible for constitutive NF-B activity, we have analyzed the inhibitor I kappa B alpha (IB) in primary and cultured HRS cells on protein, mRNA, and genomic levels. In lymph node biopsy samples from Hodgkin's disease patients, IB mRNA proved to be strongly overexpressed in the HRS cells. In 2 cell lines (L428 and KM-H2), we detected mutations in the IB gene, resulting in C-terminally truncated proteins, which are presumably not able to inhibit NF-B-DNA binding activity. Furthermore, an analysis of the IB gene in single HRS cells micromanipulated from frozen tissue sections showed a monoallelic mutation in 1 of 10 patients coding for a comparable C-terminally truncated IB protein. We suggest that the observed IB mutations contribute to constitutive NF-B activity in cultured and primary HRS cells and are therefore involved in the pathogenesis of these Hodgkin's disease (HD) patients. The demonstrated constitutive overexpression of IB in HRS cells evidences a deregulation of the NF-B/IB system also in the remaining cases, probably due to defects in other members of the IB family. © 1999 by The American Society of Hematology.     INTRODUCTION TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES THE TRANSCRIPTION FACTOR NF kappa B (NF-B) is a mediator of inducible gene expression in response to inflammatory stimuli.1,2 The NF-B family comprises 5 members (p50, p52, p65, c-rel, and RelB), which form homo- and heterodimers.3 NF-B is associated with inhibitors of the I kappa B family (IB, IB, IB, and IB), which are characterized by their ability to retain the transcription factor in an inactive complex in the cytoplasm. In response to external stimuli, IB is phosphorylated at serine residues 32 and 36 by the IB kinase complex and subsequently degraded by the ubiquitin-proteasome pathway.2,4-9 As a consequence of IB degradation, NF-B translocates into the nucleus, where it activates transcription.10 Activated NF-B induces the transcription of its own inhibitor.11 The IB protein is subsequently resynthesized and accumulates in the nucleus, where it dissociates NF-B from DNA binding and contributes to its export into the cytoplasm.12,13 Hodgkin's disease (HD) is a malignant lymphoma characterized by the presence of mononucleated Hodgkin (H) and multinucleated Reed-Sternberg (RS) cells in a background of reactive cells comprising lymphocytes, eosinophils, plasma cells, histiocytic cells, and fibroblasts.14 Recently, we identified constitutively activated NF-B (p50/p65) as a unique and common characteristic of HRS cells.15 Blocking of constitutive NF-B activity by overexpression of a dominant-negative form of IB renders HRS cells susceptible towards apoptotic stimuli and suppressed proliferation and tumor growth of HRS cells after xenotransplantation into severe combined immunodeficiency (SCID) mice.16 These data show that constitutive NF-B is required for apoptosis resistance and proliferation of HRS cells. The molecular basis for constitutive nuclear NF-B in HRS cells still needs to be investigated. The aim of this work was to identify possible molecular defects in the NF-B regulatory system of HRS cells. In hematopoietic cells, NF-B is mainly regulated by IB.17 In primary HRS cells, we found high levels of IB mRNA, indicating a persistently strong NF-B-dependent transcriptional activity. To elucidate possible molecular defects in this system, we have analyzed IB in 7 different HD-derived cell lines. In addition, the genomic sequence of IB in HRS cells from 10 HD patients was analyzed using a technique involving micromanipulation of single HRS cells and analysis by polymerase chain reaction (PCR). The analysis of 7 HD-derived cell lines showed mutations in the IB gene in 2 cell lines (L428 and KM-H2), which lead to C-terminally truncated proteins. These inhibitor variants may be responsible for constitutive NF-B activity in these cell lines. Moreover, we were able to identify a mutation in the IB gene in HRS cells from 1 patient with HD, which encodes for a comparably defective IB form. Our data provide first indications that constitutive nuclear NF-B activity in HRS cells might be a consequence of mutations in the inhibitor genes.     MATERIALS AND METHODS TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES Tissue samples and cell lines.   All cases of classic Hodgkin's disease were selected from the files of the Institute of Pathology, Free University Berlin, and classified according to the REAL classification. The HD-derived cell lines L428, L540, L591, L1236, HDLM-2, KM-H2, and HD-MyZ were maintained in RPMI 1640 (Seromed Biochrom, Berlin, Germany), 10% heat-inactivated fetal calf serum (FCS), 2 mmol/L glutamine (GIBCO, Karlsruhe, Germany), and penicillin/streptomycin (Seromed-Biochrom, Berlin, Germany); HeLa cells were grown in Dulbecco's modified Eagle's medium (DMEM) (GIBCO, Karlsruhe, Germany) supplemented with 10% FCS, 1 mmol/L sodium pyruvate, and penicillin/streptomycin. Preparation of protein and RNA extracts; Western blotting.   For protein extraction 5 × 106 cells were incubated in a lysis buffer containing proteinase inhibitors (complete, Mini, Boehringer-Mannheim, Germany). After 10 minutes of incubation at 4°C, the lysate was centrifuged for 5 minutes at 14,000 rpm in a microcentrifuge. Thirty micrograms protein extract were separated in 12% polyacrylamide gel containing sodium dodecyl sulfate (SDS) and blotted onto a nitrocellulose membrane (Schleicher & Schüll, Dassel, Germany) by electroblotting. Western blots were analyzed with chemiluminescence following the manufacturer's recommendations (ECL system, Amersham, Braunschweig, Germany). Antibodies directed against the N-terminus (C-15) and the C-terminus (C-21) of IB were obtained from SantaCruz Biotechnology Inc (Heidelberg, Germany). The RNA was prepared using the RNeasy Kit (Quiagen, Hilden, Germany) according to the manufacturer's recommendations. Amplification of IB transcripts (reverse transcriptase [RT]-PCR).   The cDNA was synthesized under the following conditions: 1 µg total RNA was incubated with 2 µL 10 × incubation buffer, 1 mmol/L each deoxyribonucleoside-triphosphate (dNTP), 5 mmol/L MgCl2, 50 U of RNAse inhibitor, and 500 ng Oligo-(dT)15 primer. After a denaturation step (65°C for 15 minutes), 20 U of avian myeloblastosis virus (AMV) RT (Boehringer-Mannheim, Germany) were added. The reaction was incubated for 1 hour at 42°C. To amplify full-length IB cDNAs, 4 different pairs of primers were designed (Table 1). The conditions for the PCR consisted of an initial denaturation step of 90 seconds at 95°C, 30 cycles of 40 seconds at 95°C, 40 seconds at 60°C, and 60 seconds at 72°C. Buffer conditions were as follows: 1.25 µmol/L MgCl2, 200 µmol/L each dNTP, 10 pmol/L of each primer, and 1 U of Taq polymerase (InViTek, Berlin, Germany).                                View this table: [in this window] [in a new window]   Table 1. Primers Used for RT-PCR of the IB mRNA Twenty microliters of each PCR was analyzed on ethidium bromide-stained agarose gels (1%) and the amplificates were isolated from the gel by the glass milk technique for DNA sequencing. Micromanipulation of single cells.   Single HRS cells were isolated from CD30 immunostained frozen sections as previously described.18 In brief, single cells were extracted by hydraulic micromanipulators from the surrounding tissue and transferred into PCR tubes with a minimal volume of buffer (0.05 to 0.1 µL) covering the tissue sections. For control, an aliquot of at least 1 µL was drawn from the buffer covering the tissue sections during the cell isolation procedure and subjected to single-copy PCR. Single-copy PCR.   To amplify the C-terminal portion of the IB gene, we designed different sets of PCR primers capable of generating 3 overlapping amplificates in a 2-step nested primer PCR (Table 2). The first PCR contained all 6 primers in 1 assay, whereas for reamplification, the 3 primer pairs were separately applied. The conditions for the first round of PCR consisted of a denaturation step of 2 minutes at 95°C, 5 cycles of 40 seconds at 95°C, 60 seconds at 58°C, and 120 seconds at 72°C, followed by 38 cycles of 40 seconds at 95°C, 60 seconds at 58°C, and 60 seconds at 72°C. The final extension lasted 10 minutes at 72°C. For reamplification, an aliquot (1.5%) of the first PCR was subjected to each of the 3 PCRs and amplified under the following conditions: an initial step of 2 minutes at 95°C and 40 cycles of 20 seconds at 95°C, 40 seconds at 58°C, and 60 seconds at 72°C followed by the final step of 10 minutes at 72°C.                                View this table: [in this window] [in a new window]   Table 2. Primers Used for Single Copy PCR of the IB Gene The same buffer conditions were used for both the first and the second amplification round: 1.5 mmol/L MgCl2, 200 µmol/L each dNTP, 8 pmol/L of each primer and 2 U of AmpliTaq (Perkin-Elmer, Weiterstadt, Germany). A total of 6 µL of each PCR was analyzed on ethidium bromide-stained agarose gels (1%), and the amplificates were isolated from the gel by the glass milk technique for DNA sequencing. DNA sequencing.   PCR products obtained from the HD-derived cell lines or from individual HRS cells were sequenced by the chain termination technique using fluorescence-labeled ddNTPs (BigDye; PE Applied Biosystems, Weiterstadt, Germany). The sequencing reactions were analyzed on an automated DNA sequencer (377A; Applied Biosystems) and the resulting sequences were compared with the sequence of the IB gene.19,20 In situ hybridization.   Radioactive in situ hybridization for the detection of IB mRNA was performed on paraffin sections. For this purpose, we generated a hybridization probe by cloning a portion of the IB cDNA (from base 540 to base 1379; M69043)19 into pKS. Radioactive-labeled run-off transcripts were prepared after linearization of the plasmid and applied to the pretreated tissue sections as previously described. In brief, dewaxed and rehydrated paraffin sections were exposed to 0.2 N HCl, 0.6 mg/mL pronase, followed by postfixation with 4% paraformaldehyde. After acetylation with 0.1 mol/L triethanolamine pH 8.0/0.25% (vol/vol) acetic anhydride and dehydration in graded ethanols, the slides were separately hybridized to 2 to 4 × 105 cpm of the labeled sense and antisense probes and left overnight at 50°C. Washing and autoradiography were performed as previously described.21     RESULTS TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES Overexpression of IB transcripts in primary HRS cells.   To examine IB mRNA expression in primary HRS cells, we performed an in situ hybridization with an IB-specific cDNA probe spanning nucleotide from base 540 to base 137919 in 20 HD cases. Most cases harbored abundant amounts of mRNA in the HRS cells (Fig 1, Table 3). In contrast to the HRS cells, only some reactive lymphocytes expressed low to moderate amounts of IB-specific transcripts (Table 3). A labeling of reactive lymphocytes with varying signal intensity was also observed in 3 cases of infectious mononucleosis. Less than 1% of the tumor cells of 5 cases of B-cell chronic lymphocytic leukemia (B-CLL) and less than 10% of the neoplastic cells of 5 cases of T-cell non-Hodgkin lymphoma (T-NHL) showed low to moderate amounts of IB mRNA. View larger version (96K): [in this window] [in a new window]   Fig 1. mRNA expression of IB in primary HRS cells of a patient with HD. (A) Hybridization with IB antisense probe. Accumulation of silver grains over HRS cells (exposure time, 6 weeks). (B) Hybridization with IB sense probe. No labeling of HRS cells.                                View this table: [in this window] [in a new window]   Table 3. Detection of IB mRNA in HRS Cells and Reactive Lymphoid Cells in 20 Cases of Classical HD by Radioactive In-Situ Hybridization L428 and KM-H2 cells express defective IB proteins due to mutations in the IB gene.   We examined IB proteins in 7 different HD-derived cell lines (L428, L540, L591, L1236, HDLM-2, KM-H2, and HD-MyZ). Western blot analysis was performed using antibodies directed against the N- and the C-terminal epitope of IB. The analysis of L428 cells with the antibody against the N-terminus showed the expression of a faster migrating IB form of about 30 kD (Fig 2A). When using the antibody directed against the C-terminus of IB, no protein was detectable in these cells (Fig 2B). Therefore, L428 cells appear to contain a C-terminally truncated form of the IB protein. In KM-H2 cells, no IB protein could be detected with both antibodies. The 5 remaining HD-derived cell lines (L540, L591, L1236, HD-LM2, and HD-MyZ) showed expression of full-length IB proteins of 38 kD (Fig 2). View larger version (36K): [in this window] [in a new window]   Fig 2. Western blot analysis of IB proteins in HD-derived cell lines. Whole-cell extracts were analyzed using specific antibodies against the N-terminus (A) and the C-terminus (B) of IB. Specific protein bands are indicated by an arrow and the truncated form in L428 cells (IBC) is marked with a dot. Next, we analyzed the IB mRNA and the IB gene in HD-derived cell lines. Transcripts for IB were amplified by RT-PCR and sequenced. In L428 and KM-H2 cells, we detected mutated IB transcripts. L428 cells showed a point mutation at nucleotide position (pos) 893 of the human cDNA19 generating a preterminal stop codon (Fig 3A). When we examined KM-H2 cells, we detected 2 deletions, 1 between pos 509 and pos 613 and another between pos 618 and pos 640 (Fig 3B). These deletions result in a frame shift and are followed by a preterminal stop at pos 715. Genomic sequencing showed that the observed alterations are due to mutations in the IB gene. The genomic PCR detected only mutant and no wild-type IB sequences. These data show that the occurrence of defects of IB proteins in HRS cells is a consequence of mutations in the IB gene. In accordance with the Western blot data in both cell lines, the mutant forms of IB were expressed exclusively and no transcripts of wild-type IB were detectable. View larger version (41K): [in this window] [in a new window]   Fig 3. Structure of mutant cDNA transcripts for IB in L428 (A) cells and KM-H2 (B) cells and scheme of the predicted truncated IB proteins. The ankyrin repeats required for the interaction with NF-B are indicated by filled boxes. (A) A point mutation at pos 893 of the IB cDNA sequence in L428 cells generates a preterminal stop as indicated. (B) Top panel: 2 deletions between pos 509 and 613 and pos 618 and 640 of the IB cDNA in KM-H2 cells result in a frame shift followed by a preterminal stop codon at pos 715. Bottom panel: Alignment of the wild-type (w.t.) cDNA sequence of IB and the mutant IB sequence in KM-H2 cells. Deletions and the resulting frame shift are indicated. Analysis of the IB gene in single HRS cells.   To investigate whether IB mutations could also be detected in primary HRS cells, we analyzed single HRS cells from lymph node biopsy samples from patients with HD. A total of 420 individual HRS cells were isolated from frozen sections of 10 patients, and the part of the IB gene comprising the mutations in the cell lines (2283 nt to 4391 nt)20 was divided into 3 parts and amplified by PCR. Between 5 and 11 PCR products were obtained from each amplified region, sequenced, and compared with the IB gene sequence. In 1 case, we detected a point mutation in exon V (pos 3398; TGT  TGA) causing a stop codon, with the consequence of a preterminal breakage of the protein synthesis at amino acid 214 (Table 4; Fig 4). From 72 HRS cells of this case, 22 PCR products were obtained, 11 of which comprised the affected 3'-region of the IB gene. In 4 of 11 cells, we detected the stop codon exclusively, whereas an additional 4 cells contained both the mutant and the wild-type IB gene. This alteration did not occur in the remaining 3 HRS cells. This finding indicated that only 1 allele harbored the stop codon, whereas the other allele was wild-type. The IB gene of reactive bystander lymphocytes isolated from the same biopsy tissue showed no alteration, indicating that this stop codon was restricted to the HRS cells.                                View this table: [in this window] [in a new window]   Table 4. Detection of Mutations in the Intron and Exon Regions of the IB Gene in Single HRS Cells View larger version (15K): [in this window] [in a new window]   Fig 4. Structure of the expected mutant IB cDNA sequence in a patient with HD. Top panel: Alignment of the expected w.t. cDNA sequence of IB and the predicted mutant IB sequence in primary HRS cells. A point mutation at pos 739 generates a preterminal stop. Bottom panel: Presumable structure of the resulting truncated IB protein in primary HRS cells. The ankyrin repeats required for the interaction with NF-B are indicated by filled boxes. Base substitutions in the introns were detectable in all cases, as well as in reactive lymphocytes (Table 4). However, because these modifications do not affect the coding sequence, they most likely represent irrelevant interindividual variations. In addition, the same silent base substitution was found in exon II of 4 cases (Table 4), indicative of an interindividual polymorphism.     DISCUSSION TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES The aim of this work was to identify molecular defects in the NF-B regulatory system leading to constitutive NF-B activation in HRS cells. In IB/ mice, constitutive NF-B activation could be observed in lymphoid cells.17 Hence, this inhibitor appears to play a major role in regulating NF-B activity in the lymphoid system. In cultured HRS cells, mRNAs for IB are strongly overexpressed.15 To test if this is also valid for primary HRS cells, we examined 20 cases of classic HD by a highly sensitive radioactive in situ hybridization with an IB-specific cDNA probe. In all cases, we detected overexpression of IB mRNA in the HRS cells, whereas in normal lymphoid tissues and in cases of B-CLL and T-cell NHL, no or very little amounts of IB mRNA were found. Therefore, high levels of IB are a highly characteristic feature of cultured and primary HRS cells. Because NF-B activates transcription of its own inhibitor, this finding reflects the high transcriptional activity of NF-B in this lymphoid malignancy.11 It has been demonstrated that enforced expression of IB leads to accumulation of the protein in the nucleus.12 Nuclear IB is involved in the export of NF-B into the cytoplasm, thus contributing to the termination of NF-B activity.13 The paradoxical finding of high NF-B activity despite the strong expression of its inhibitor indicates that the NF-B/IB system is severely deregulated in HRS cells. A mechanism leading to this loss of control could be a defect of the IB molecule. To investigate this possibility, we analyzed IB transcripts in 7 HD-derived cell lines and found a disruption of the coding sequence by a stop codon in the cell line L428, and by 2 deletions followed by a stop codon in the cell line KM-H2. These mutations found in the RNA were confirmed by genomic sequencing, disclosing the existence of only mutated IB genes in the absence of wild-type alleles. In accordance with these sequence data, we detected expression of exclusively C-terminally truncated proteins in both cell lines consistent with previous reports.22,23 To analyze whether comparable IB mutations also occur in primary HRS cells, we isolated single HRS cells from CD30 immunostained tissue sections of 10 HD patients and analyzed the IB gene by single cell PCR. The IB gene of 1 case (case 1; Table 4) contained a mutation generating a preterminal stop of the translational machinery. The expected mRNA codes for a C-terminally truncated protein of about 214 amino acids comparable to that found in L428 cells. This stop codon was not found in nonmalignant lymphoid bystander cells of the same case, indicating that this mutation was specific for the HRS cells. No disruptive alterations were detectable in the IB genes of the HRS cells in the remaining 9 HD cases. In contrast to cell lines with only mutant genomic sequences (L428 and KM-H2), the mutated HRS cells of case 1 contained both mutant and wild-type sequences, suggesting a monoallelic mutation of IB and presumably leading to coexpression of mutant and wild-type IB proteins. This raises the question as to the functional significance of this monoallelic mutation. It is well conceivable that the C-terminally truncated protein can block the wild-type protein. Aside from its function of retaining NF-B in the cytoplasm, IB can localize in the nucleus and dissociate NF-B-DNA complexes.13 A prerequisite for effective inhibition of NF-B-DNA binding are the ankyrin repeats and an intact C-terminus, in which IB is constitutively phosphorylated at serine and threonine residues by casein kinase II.24-27 A role of the C-terminal end for the inhibition of NF-B-DNA binding has recently been suggested by an x-ray structure analysis of the NF-B/IB complex.28,29 Furthermore, IB contains a nuclear export signal (NES) at amino acids 264-281, which confers active shuttling of the NF-B/IB complex to the cytosol.13,20 Therefore, the functionally defective truncated IB may protect DNA-bound NF-B from dissociation by wild-type IB and interfere with the nuclear export pathway. As a consequence of this process NF-B-DNA binding activity would be maintained in HRS cells. Although the observed mutation is found only in 1 of 10 cases, our data provide the first indication that permanently activated NF-B in primary HRS cells might be a consequence of gene mutations of one of its inhibitors. Studies on constitutive NF-B activity have shown that a hypophosphorylated form IB shields NF-B from IB-mediated inhibition and plays an important role in permanent NF-B activation. It is therefore tempting to speculate that defects of additional members of the IB family contribute to the functional blockage of IB in the remaining cases. Further expression and molecular studies are required to investigate this possibility.     NOTE ADDED IN PROOF During the review process, a report that was submitted after ours has appeared dealing with the analysis of IB mutations in enriched RS cells. The investigators described IB mutations in 2 of 8 HD cases, which cause a preterminal truncation of the IB protein.30     FOOTNOTES Submitted March 8, 1999; accepted July 2, 1999. Supported by a grant of the Deutsche Forschungsgemeinschft (DFG; Ste 318/5-2). The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact. Address reprint requests to Harald Stein, MD, Institute of Pathology, Benjamin Franklin University Hospital, Free University Berlin, Hindenburgdamm 30, 12200 Berlin, Germany; e-mail: stein{at}ukbf.fu-berlin.de.     REFERENCES TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES 1. Baeuerle PA, Henkel T: Function and activation of NF-B in the immune system. Annu Rev Immunol 12:141, 1994[Medline] [Order article via Infotrieve] 2. Wulczyn FG, Krappmann D, Scheidereit C: The NF-B and IB gene families: Mediators of immune response and inflammation. J Mol Med 74:749, 1996[Medline] [Order article via Infotrieve] 3. Baeuerle P, Baltimore D: NF-B: Ten years after. Cell 87:13, 1996[Medline] [Order article via Infotrieve] 4. Traencker EB, Wilk S, Baeuerle P: A proteasome inhibitor prevents activation of NF-B. EMBO J 13:5433, 1994[Medline] [Order article via Infotrieve] 5. Brockman JA, Scherer DC, McKinsey TA, Hall SM, Qi X, Lee WY, Ballard DW: Coupling of a signal response domain in IB to multiple pathways for NF-B activation. Mol Cell Biol 15:2809, 1995[Abstract] 6. Brown KS, Gerstberger L, Carlson G, Franzose U, Siebenlist U: Control of IB proteolysis by site-specific, signal-induced phosphorylation. Science 267:1485, 1995[Abstract/Free Full Text] 7. Scherer DC, Brockman ZJ, Chen T, Maniatis T, Balard DW: Signal-induced degradation of IB requires site-specific ubiquitination. Proc Natl Acad Sci USA 92:11259, 1995[Abstract/Free Full Text] 8. Whiteside ST, Ernst MK, LeBail O, Laurent-Winter C, Rice N, Israel A: N- and C-terminal sequences control degradation of MAD3/ IB in response to inducers of NF-B activity. Mol Cell Biol 15:5339, 1995[Abstract] 9. Sun SC, Elwood J, Greene WC: Both amino- and carboxy-terminal sequences within IB regulate its inducible degradation. Mol Cell Biol 16:1058, 1996[Abstract] 10. Baldwin AS: The NF-kappa B and I kappa B proteins: New discoveries and insights. Annu Rev Immunol 14:649, 1996[Medline] [Order article via Infotrieve] 11. Sun SC, Ganchi PA, Ballard DW, Greene WC: NF-kappa B controls expression of inhibitor I kappa B alpha: Evidence for an inducible autoregulatory pathway. Science 259:1912, 1993[Abstract/Free Full Text] 12. Arenzana-Seisdedos F, Thompson J, Rodriguez MS, Bachelerie F, Thomas D, Hay RT: Inducible nuclear expression of newly synthesized IB negatively regulates DNA binding and transcriptional activities of NF-B. Mol Cell Biol 15:2689, 1995[Abstract] 13. Arenzana-Seisdedos F, Turpin P, Rodriguez M, Thomas D, Hay RT, Virelizier J-L, Dargemont C: Nuclear localization of IB promotes active transport of NF-B from the nucleus to the cytoplasm. J Cell Sci 110:369, 1997[Abstract] 14. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JKC, Cleary ML, Delsol G, DeWolf-Peeters C, Falini B, Gatter KC, Grogan TM, Isaacson PG, Knowles DM, Mason DY, Muller-Hermelink H-K, Pileri SA, Piris MA, Ralfkiaer E, Warnke RA: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361, 1994[Free Full Text] 15. Bargou RC, Leng C, Krappmann D, Emmerich F, Mapara MY, Bommert K, Royer HD, Scheidereit C, Dörken B: High-level nuclear NF-B and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells. Blood 87:4340, 1996[Abstract/Free Full Text] 16. Bargou RC, Emmerich F, Krappmann D, Bommert K, Mapara MY, Arnold W, Royer HD, Grinstein E, Greiner A, Scheidereit C, Dörken B: Constitutive NF-B-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells. J Clin Invest 100:2961, 1997[Medline] [Order article via Infotrieve] 17. Beg AA, Sha WC, Bronson RT, Baltimore D: Constitutive activation, enhanced granulopoiesis and neolethal lethality in IB-deficient mice. Genes Dev 9:2736, 1995[Abstract/Free Full Text] 18. Marafioti T, Hummel M, Anagnostopoulos I, Foss HD, Falini B, Desol G, Isaacson PG, Pileri S, Stein H: Origin of nodular lymphocyte-predominant Hodgkin's disease from a clonal expansion of highly mutated germinal center B cells. N Engl J Med 337:453, 1997[Abstract/Free Full Text] 19. Haskill S, Beg AA, Tompkins SM, Morris JS, Yurochko AD, Sampson-Johannes A, Mondal K, Ralph P, Baldwin AS Jr: Characterization of an immediate-early gene induced in adherent monocytes that encodes I kappa B-like activity. Cell 65:1281, 1991[Medline] [Order article via Infotrieve] 20. Ito CY, Adey N, Bautch VL, Baldwin AS Jr: Structure and evolution of the IB gene. Genomics 29:490, 1995[Medline] [Order article via Infotrieve] 21. Foss HD, Hummel M, Gottstein S, Ziemann K, Falini B, Herbst H, Stein H: Frequent expression of IL-7 gene transcripts in tumor cells of classical Hodgkin's disease. Am J Pathol 146:33, 1995[Abstract] 22. Krappmann D, Emmerich F, Kordes U, Scharschmidt E, Dörken B, Scheidereit C: Molecular mechanisms of aberrant constitutive NF-B/Rel activation in Hodgkin/Reed-Sternberg cells. Oncogene 18:943, 1999[Medline] [Order article via Infotrieve] 23. Wood KM, Roff M, Hay R: Defective IB in Hodgkin cell lines with constitutively active NF-B. Oncogene 16:2131, 1998[Medline] [Order article via Infotrieve] 24. Hatada EN, Naumann M, Scheidereit C: Common structural constituents confer I kappa B activity to NF kappa B/p105 and I kappa B/MAD3. EMBO J 12:2781, 1993[Medline] [Order article via Infotrieve] 25. Ernst MK, Dunn LL, Rice NR: The PEST-like sequence if I kappa B alpha is responsible for inhibition of DNA binding but not for cytoplasmatic retention of c-Rel or RelA homodimers. Mol Cell Biol 15:872, 1995[Abstract] 26. Barroga CF, Stevenson JK, Schwarz EM, Verma IM: Constitutive phosphorylation of IB by casein kinase II. Proc Natl Acad Sci 92:7637, 1995[Abstract/Free Full Text] 27. Liu L, Kwak YT, Bex F, Garcia-Martinez LF, Li XH, Meek K, Lane WS, Gaynor RB: DNA-dependant protein kinase phosphorylation of IB and IB regulates NF-B binding properties. Mol Cell Biol 18:4221, 1998[Abstract/Free Full Text] 28. Jacobs MD, Harrison S: Structure of the IB/ NF-B complex. Cell 95:749, 1998[Medline] [Order article via Infotrieve] 29. Huxford T, Huang DB, Malek S, Gosh G: The crystal structure of the IB/ NF-B complex reveals mechanisms of NF-B inactivation. Cell 95:759, 1998[Medline] [Order article via Infotrieve] 30. Cabannes E, Khan G, Aillet F, Jarrett RF, Hay RT: Mutations in the IB gene in Hodgkin's disease suggest a tumor suppressor role for IB. 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Pathol., May 1, 2002; 160(5): 1647 - 1654. [Abstract] [Full Text] [PDF] F. Jundt, I. Anagnostopoulos, R. Forster, S. Mathas, H. Stein, and B. Dorken Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma Blood, May 1, 2002; 99(9): 3398 - 3403. [Abstract] [Full Text] [PDF] R. K. Thomas, A. Kallenborn, C. Wickenhauser, J. L. Schultze, A. Draube, M. Vockerodt, D. Re, V. Diehl, and J. Wolf Constitutive Expression of c-FLIP in Hodgkin and Reed-Sternberg Cells Am. J. Pathol., April 1, 2002; 160(4): 1521 - 1528. [Abstract] [Full Text] [PDF] S A Pileri, S Ascani, L Leoncini, E Sabattini, P L Zinzani, P P Piccaluga, A Pileri Jr, M Giunti, B Falini, G B Bolis, et al. Hodgkin's lymphoma: the pathologist's viewpoint J. Clin. Pathol., March 1, 2002; 55(3): 162 - 176. [Abstract] [Full Text] [PDF] J. I. Martin-Subero, S. Gesk, L. Harder, T. Sonoki, P. W. Tucker, B. Schlegelberger, W. Grote, F. J. Novo, M. J. Calasanz, M. L. 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Diabetes-Associated Sustained Activation of the Transcription Factor Nuclear Factor-{kappa}B Diabetes, December 1, 2001; 50(12): 2792 - 2808. [Abstract] [Full Text] [PDF] R. Romieu-Mourez, E. Landesman-Bollag, D. C. Seldin, A. M. Traish, F. Mercurio, and G. E. Sonenshein Roles of IKK Kinases and Protein Kinase CK2 in Activation of Nuclear Factor-{{kappa}}B in Breast Cancer Cancer Res., May 1, 2001; 61(9): 3810 - 3818. [Abstract] [Full Text] M. Hinz, P. Loser, S. Mathas, D. Krappmann, B. Dorken, and C. Scheidereit Constitutive NF-{kappa}B maintains high expression of a characteristic gene network, including CD40, CD86, and a set of antiapoptotic genes in Hodgkin/Reed-Sternberg cells Blood, May 1, 2001; 97(9): 2798 - 2807. [Abstract] [Full Text] [PDF] J. Witowski, A. Thiel, R. Dechend, K. Dunkel, N. Fouquet, T. O. Bender, J. M. Langrehr, G. M. Gahl, U. Frei, and A. Jorres Synthesis of C-X-C and C-C Chemokines by Human Peritoneal Fibroblasts : Induction by Macrophage-Derived Cytokines Am. J. Pathol., April 1, 2001; 158(4): 1441 - 1450. [Abstract] [Full Text] [PDF] S. S. Mir, B. W. M. Richter, and C. S. Duckett Differential effects of CD30 activation in anaplastic large cell lymphoma and Hodgkin disease cells Blood, December 15, 2000; 96(13): 4307 - 4312. [Abstract] [Full Text] [PDF] C. M. Annunziata, Y. J. Safiran, S. G. Irving, U. N. Kasid, and J. Cossman Hodgkin disease: pharmacologic intervention of the CD40-NFkappa B pathway by a protease inhibitor Blood, October 15, 2000; 96(8): 2841 - 2848. [Abstract] [Full Text] [PDF] P. Rameshwar, R. Narayanan, J. Qian, T. N. Denny, C. Colon, and P. Gascon NF-{kappa}B as a Central Mediator in the Induction of TGF-{beta} in Monocytes from Patients with Idiopathic Myelofibrosis: An Inflammatory Response Beyond the Realm of Homeostasis J. Immunol., August 15, 2000; 165(4): 2271 - 2277. 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