The HIN-200 family: More than interferon-inducible genes?

doi:10.1016/j.yexcr.2005.03.032

Experimental Cell Research

Volume 308, Issue 1, 1 August 2005, Pages 1-17

https://doi.org/10.1016/j.yexcr.2005.03.032 Get rights and content

Abstract

The HIN-200 family was initially grouped together based on their hemopoietic expression, interferon-inducibility, nuclear localization, and characteristic 200 amino-acid domains. In this review, we performed a comprehensive search of genome databases and determined the location of previously characterized and predicted genes within the human, mouse, and rat HIN-200 loci. Several novel proteins were predicted in the mouse and rat. We also discuss recent advances in our understanding of this family of proteins and highlight the most important findings.

In addition to a role in interferon biology, there is now good evidence supporting a role for these proteins as regulators of cell proliferation and differentiation. The activity of HIN-200 proteins is not restricted to the hemopoietic system as they are expressed and can function in a variety of other cells and tissues. The importance of HIN-200 proteins in disease now is beginning to be understood as they appear to be involved in autoimmunity and may act as tumor suppressor proteins.

Introduction

The first murine HIN-200 gene, Ifi 202a, was identified in 1982, and since then, a family of five murine and four human interferon-inducible family members has been cloned and characterized. Murine HIN-200 proteins include p202a (previously referred to as p202), p202b, p203, p204, and p205 (originally named D3) while the human HIN-200 family members comprise IFI 16 (Interferon-Inducible protein 16), MNDA (Myeloid Nuclear Differentiation Antigen), AIM2 (Absent In Melanoma 2), and IFIX (IFN-inducible protein X). These proteins were initially grouped as a family because they contain conserved structural domains and motifs and are induced by IFN. Later, the HIN-200 nomenclature was adopted describing their hemopoietic expression, IFN-induction, nuclear localization, and characteristic 200 amino-acid domains. In this review, we propose that the 200 amino-acid domains be referred to as “200 X domains” where X represents the subclass of this domain and can be either A, B, or the C subclass newly identified in this review (refer to the Reclassification of the 200 X domains section for more information). Recent research in the field has revealed that the HIN-200 classification though accurate in some respects, is not appropriate for all the family members. HIN-200 proteins have a wider cellular distribution than originally thought, can be regulated by a range of exogenous stimuli other than IFN, and are not exclusively found in the nucleus. The molecular, biochemical, and biological characteristics of each family member have been assessed to varying extents and point to a role in the regulation of cell proliferation and differentiation. However, established methods for defining the physiological functions of genes such as transgenic and knock-out mouse models have not yet been successfully employed for this gene family. While all HIN-200 proteins are induced by type I and type II IFN, their role in IFN biology has not been established, and more recently, interest in the HIN-200 proteins has centered on their proposed role in autoimmunity and cancer. No true structural and functional mouse homologues of human HIN-200 proteins have been identified, but it remains possible that such homologues and other HIN-200 genes exist and await discovery. In this review, we have analyzed the location of known genes within the human and mouse HIN-200 loci and identified novel computer predicted mouse and rat HIN-200 genes. In addition, we provide an update on the functional properties of HIN-200 proteins.

Section snippets

Previously identified HIN-200 genes

The murine HIN-200 genes represent one of the earliest identified families of IFN-responsive genes following the discovery of the MHC cluster in 1986 [1]. Of the five known murine HIN-200 genes, Ifi 202a [2], Ifi 203 [3], and Ifi 204 [4] were cloned in screens for IFN-responsive genes and Ifi 205 was identified in a screen for lipopolysaccharide (LPS)-responsive genes [5]. The Ifi 202b gene is almost identical to Ifi 202a, suggesting that they may have arisen by gene duplications. Ifi 202b and

Protein structure of known and novel proteins

As shown in Fig. 4, the known HIN-200 proteins have a conserved domain structure. With the exception of p202a and p202b, they all contain a PAAD/DAPIN/Pyrin domain at their N-termini and, with the exception of the IFIXγ isoform, this is followed by either one or two copies of a C-terminal 200 X domain. The intervening ‘spacer’ regions that separate these domains in certain HIN-200 proteins are not conserved in overall sequence and size, but are rich in S/T/P residues indicating a common

Subcellular localization

HIN-200 proteins are normally localized to the nucleus. In some cases, nuclear import is mediated by a recognized nuclear localization signal (NLS), for example, p203, p204, p205, and IFIX contain basic amino-acid residues at their N-terminus and IFI 16 has a bipartite NLS [37]. The molecular events underpinning nuclear localization of p202a, AIM2, and MNDA are less clear as no recognized NLS is present in these proteins. For selected family members, localization can be assigned to specific

Function of HIN-200 proteins

Two attempts have been made to genetically manipulate HIN-200 genes in the mouse. Firstly, production of transgenic animals over-expressing p204 was attempted by expression of the Ifi 204 cDNA under control of the SV40 promoter in C57Bl/6 mice. No viable animals were produced because cell development was blocked at the four-cell stage [57]. Secondly, knock-out of Ifi 202a by homologous recombination was achieved; however, the highly homologous Ifi 202b gene was up-regulated to compensate for

Conclusions and perspectives

In this study, we have used genomic database resources to map the human, mouse, and rat HIN-200 loci and have reviewed recent developments in the field of HIN-200 biology. Using this approach, we have comprehensively mapped the existing characterized HIN-200 genes and have predicted three novel rat and four novel mouse HIN-200 genes. The reason for the existence of such a large number of HIN-200 genes is not known. Interestingly, we have identified direct homologues of AIM2 in the mouse and rat

Acknowledgments

The authors would like to acknowledge Scott Fraser, Rachael Roberts, Steven Williams, Sheena Wong, and Sharon Wright for their input into the sequence analysis of the human, mouse, and rat HIN-200 genes. R.W.J. is a Welcome Trust Senior fellow. L.L. is supported by an Australian Postgraduate Award from The University of Melbourne, Australia. This work was funded by a program grant from the NHMRC of Australia.

References (99)

R.A. Flavell et al.
Molecular biology of the H-2 histocompatibility complex
Science
(1986)
D.A. Engel et al.
Interferon action: transcriptional control of a gene specifying a 56,000-Da protein in Ehrlich ascites tumor cells
Virology
(1985)
G. Gribaudo et al.
Molecular cloning and expression of an interferon-inducible protein encoded by gene 203 from the gene 200 cluster
Eur. J. Biochem.
(1997)
D.A. Engel et al.
Interferons as gene activators: close linkage of two interferon-activatable murine genes
Virology
(1988)
T.A. Hamilton et al.
IFN-gamma and IFN-beta independently stimulate the expression of lipopolysaccharide-inducible genes in murine peritoneal macrophages
J. Immunol.
(1989)
H. Wang et al.
Characteristics of three homologous 202 genes (Ifi202a, Ifi202b, and Ifi202c) from the murine interferon-activatable gene 200 cluster
Genomics
(1999)
J.A. Trapani et al.
A novel gene constitutively expressed in human lymphoid cells is inducible with interferon-gamma in myeloid cells
Immunogenetics
(1992)
A. Goldberger et al.
Nonhistone protein antigen profiles of five leukemic cell lines reflect the extent of myeloid differentiation
Blood
(1984)
K.L. DeYoung et al.
Cloning a novel member of the human interferon-inducible gene family associated with control of tumorigenicity in a model of human melanoma
Oncogene
(1997)
M.E. Ray et al.
Isolation and characterization of genes associated with chromosome-6 mediated tumor suppression in human malignant melanoma
Oncogene
(1996)

Y. Ding et al.

Antitumor activity of IFIX, a novel interferon-inducible HIN-200 gene, in breast cancer

Oncogene

(2004)

R.C. Briggs et al.

The human myeloid cell nuclear differentiation antigen gene is one of at least two related interferon-inducible genes located on chromosome 1q that are expressed specifically in hematopoietic cells

Blood

(1994)

G. Opdenakker et al.

Interferons as gene activators: a cluster of six interferon-activatable genes is linked to the erythroid alpha-spectrin locus on murine chromosome 1

Virology

(1989)

L.D. Stein

Human genome: end of the beginning

Nature

(2004)

B. Asefa et al.

The interferon-inducible p200 family of proteins: a perspective on their roles in cell cycle regulation and differentiation

Blood Cells Mol. Dis.

(2004)

S. Deschamps et al.

The mouse Ifi200 gene cluster: genomic sequence, analysis, and comparison with the human HIN-200 gene cluster

Genomics

(2003)

T. Shiina et al.

Genomic anatomy of a premier major histocompatibility complex paralogous region on chromosome 1q21–q22

Genome Res.

(2001)

D. Koul et al.

p202 self-associates through a sequence conserved among the members of the 200-family proteins

FEBS Lett.

(1998)

D. Choubey et al.

Binding of an interferon-inducible protein (p202) to the retinoblastoma protein

J. Biol. Chem.

(1995)

J.C. Reed et al.

Comparative analysis of apoptosis and inflammation genes of mice and humans

Genome Res.

(2003)

K. Pawlowski et al.

PAAD—A new protein domain associated with apoptosis, cancer and autoimmune diseases

Trends Biochem. Sci.

(2001)

E. Staub et al.

The DAPIN family: a novel domain links apoptotic and interferon response proteins

Trends Biochem. Sci.

(2001)

R.W. Johnstone et al.

Isotypic variants of the interferon-inducible transcriptional repressor IFI 16 arise through differential mRNA splicing

Biochemistry

(1998)

J. Xie et al.

MNDA dimerizes through a complex motif involving an N-terminal basic region

FEBS Lett.

(1997)

K.S. Cresswell et al.

Biochemical and growth regulatory activities of the HIN-200 family member and putative tumor suppressor protein, AIM2

Biochem. Biophys. Res. Commun.

(2005)

M.J. Dawson et al.

The interferon-inducible autoantigen, IFI 16: localization to the nucleolus and identification of a DNA-binding domain

Biochem. Biophys. Res. Commun.

(1995)

T. Liu et al.

Homology modeling provides insights into the binding mode of the PAAD/DAPIN/pyrin domain, a fourth member of the CARD/DD/DED domain family

Protein Sci.

(2003)

D. Choubey et al.

The interferon-inducible growth-inhibitory p202 protein: DNA binding properties and identification of a DNA binding domain

Biochem. Biophys. Res. Commun.

(1996)

M. Albrecht et al.

The HIN domain of IFI-200 proteins consists of two OB folds

Biochem. Biophys. Res. Commun.

(2005)

B. Datta et al.

p202, an interferon-inducible modulator of transcription, inhibits transcriptional activation by the p53 tumor suppressor protein, and a segment from the p53-binding protein 1 that binds to p202 overcomes this inhibition

J. Biol. Chem.

(1996)

R.W. Johnstone et al.

The human interferon-inducible protein, IFI 16, is a repressor of transcription

J. Biol. Chem.

(1998)

R.W. Johnstone et al.

Functional interaction between p53 and the interferon-inducible nucleoprotein IFI 16

Oncogene

(2000)

X.Y. Ma et al.

The interferon-inducible p202a protein modulates NF-kappaB activity by inhibiting the binding to DNA of p50/p65 heterodimers and p65 homodimers while enhancing the binding of p50 homodimers

J. Biol. Chem.

(2003)

S. Landolfo et al.

The Ifi 200 genes: an emerging family of IFN-inducible genes

Biochimie

(1998)

J.M. Dermott et al.

Inhibition of growth by p205: a nuclear protein and putative tumor suppressor expressed during myeloid cell differentiation

Stem Cells

(2004)

C.S. Tannenbaum et al.

A lipopolysaccharide-inducible macrophage gene (D3) is a new member of an interferon-inducible gene cluster and is selectively expressed in mononuclear phagocytes

J. Leukocyte Biol.

(1993)

L.J. Briggs et al.

Novel properties of the protein kinase CK2-site-regulated nuclear- localization sequence of the interferon-induced nuclear factor IFI 16

Biochem. J.

(2001)

D. Choubey et al.

Interferon action: nucleolar and nucleoplasmic localization of the interferon-inducible 72-kD protein that is encoded by the Ifi 204 gene from the gene 200 cluster

J. Cell Biol.

(1992)

D. Choubey et al.

Cytoplasmic localization of the interferon-inducible protein that is encoded by the AIM2 (absent in melanoma) gene from the 200-gene family

FEBS Lett.

(2000)

D. Choubey et al.

Interferon action: cytoplasmic and nuclear localization of the interferon-inducible 52-kD protein that is encoded by the Ifi 200 gene from the gene 200 cluster

J. Interferon Res.

(1993)

D. Choubey et al.

Subcellular localization and mechanisms of nucleocytoplasmic distribution of p202, an interferon-inducible candidate for lupus susceptibility

FEBS Lett.

(2003)

C. Liu et al.

MyoD-dependent induction during myoblast differentiation of p204, a protein also inducible by interferon

Mol. Cell Biol.

(2000)

H. Xin et al.

Role of IFI 16, a member of the interferon-inducible p200-protein family, in prostate epithelial cellular senescence

Oncogene

(2003)

M. Gariglio et al.

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

J. Leukocyte Biol.

(1998)

W. Wei et al.

Expression of IFI 16 in epithelial cells and lymphoid tissues

Histochem. Cell Biol.

(2003)

M. Gariglio et al.

Immunohistochemical expression analysis of the human interferon-inducible gene IFI16, a member of the HIN200 family, not restricted to hematopoietic cells

J. Interferon Cytokine Res.

(2002)

R.N. Miranda et al.

Immunocytochemical analysis of MNDA in tissue sections and sorted normal bone marrow cells documents expression only in maturing normal and neoplastic myelomonocytic cells and a subset of normal and neoplastic B lymphocytes

Hum. Pathol.

(1999)

M.J. Dawson et al.

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

J. Leukocyte Biol.

(1998)

M.J. Dawson et al.

The closely linked genes encoding the myeloid nuclear differentiation antigen (MNDA) and IFI16 exhibit contrasting haemopoietic expression

Immunogenetics

(1995)

Cited by (142)

New insights into nucleic acid sensor AIM2: The potential benefit in targeted therapy for cancer
2024, Pharmacological Research
The AIM2 inflammasome represents a multifaceted oligomeric protein complex within the innate immune system, with the capacity to perceive double-stranded DNA (dsDNA) and engage in diverse physiological reactions and disease contexts, including cancer. While originally conceived as a discerning DNA sensor, AIM2 has demonstrated its capability to discern various nucleic acid variations, encompassing RNA and DNA-RNA hybrids. Through its interaction with nucleic acids, AIM2 orchestrates the assembly of a complex involving multiple proteins, aptly named the AIM2 inflammasome, which facilitates the enzymatic cleavage of proinflammatory cytokines, namely pro-IL-1β and pro-IL-18. This process, in turn, underpins its pivotal biological role. In this review, we provide a systematic summary and discussion of the latest advancements in AIM2 sensing various types of nucleic acids. Additionally, we discuss the modulation of AIM2 activation, which can cause cell death, including pyroptosis, apoptosis, and autophagic cell death. Finally, we fully illustrate the evidence for the dual role of AIM2 in different cancer types, including both anti-tumorigenic and pro-tumorigenic functions. Considering the above information, we uncover the therapeutic promise of modulating the AIM2 inflammasome in cancer treatment.
Prognostic value of anti-IFI16 autoantibodies in pulmonary arterial hypertension and mortality in patients with systemic sclerosis
2024, Medicina Clinica
To determine the diagnostic value of anti-interferon gamma inducible protein 16 (IFI16) autoantibodies in systemic sclerosis (SSc) patients negative for all tested SSc-specific autoantibodies (SSc-seronegative patients) and to evaluate the clinical significance of these autoantibodies, whether isolated or in the presence of anti-centromere autoantibodies (ACA).
Overall, 58 SSc-seronegative and 66 ACA-positive patients were included in the study. All patients were tested for anti-IFI16 autoantibodies by an in-house direct ELISA. Associations between clinical parameters and anti-IFI16 autoantibodies were analysed.
Overall, 17.2% of SSc-seronegative and 39.4% of ACA-positive patients were positive for anti-IFI16 autoantibodies. Anti-IFI16 autoantibodies were found only in patients within the limited cutaneous SSc (lcSSc) subset. A positive association between anti-IFI16 positivity and isolated pulmonary arterial hypertension (PAH) was found (odds ratio [OR] = 5.07; p = 0.014) even after adjusting for ACA status (OR = 4.99; p = 0.019). Anti-IFI16-positive patients were found to have poorer overall survival than negative patients (p = 0.032). Cumulative survival rates at 10, 20 and 30 years were 96.9%, 92.5% and 68.7% for anti-IFI16-positive patients vs. 98.8%, 97.0% and 90.3% for anti-IFI16-negative-patients, respectively. Anti-IFI16-positive patients also had worse overall survival than anti-IFI16-negative patients after adjusting for ACA status in the multivariate Cox analysis (hazard ratio [HR] = 3.21; p = 0.043).
Anti-IFI16 autoantibodies were associated with isolated PAH and poorer overall survival. Anti-IFI16 autoantibodies could be used as a supplementary marker of lcSSc in SSc-seronegative patients and for identifying ACA-positive patients with worse clinical outcome.
Determinar el valor diagnóstico de los autoanticuerpos anti-interferon gamma inducible protein 16 (IFI16) en los pacientes con esclerodermia sistémica (SSc) negativos para todos los autoanticuerpos específicos de SSc (pacientes SSc seronegativos) y evaluar el significado clínico de estos autoanticuerpos, aislados o en combinación con autoanticuerpos anticentrómero (ACA).
Se incluyeron 58 pacientes SSc seronegativos y 66 pacientes ACA positivos. Todos los pacientes se testaron para los autoanticuerpos anti-IFI16 mediante un ELISA directo «in-house». Las asociaciones entre parámetros clínicos y los autoanticuerpos anti-IFI16 fueron analizadas.
En total, el 17,2% de los pacientes SSc seronegativos y el 39,4% de los pacientes ACA positivos fueron positivos para anti-IFI16. Los autoanticuerpos anti-IFI16 se detectaron solamente en los pacientes con la forma limitada cutánea de SSc (lcSSc). Se encontró una asociación entre la positividad de anti-IFI16 y la hipertensión arterial pulmonar (HAP) aislada (odds ratio [OR]: 5,07; p = 0,014), incluso cuando se ajustó el análisis a la presencia o ausencia de ACA (OR: 4,99; p = 0,019). Los pacientes anti-IFI16 positivos mostraron una peor supervivencia general que los pacientes negativos (p = 0,032). Las ratios de supervivencia acumulada a 10, 20 y 30 años fueron respectivamente del 96,9, 92,5 y 68,7% para los pacientes anti-IFI16 positivos frente al 98,8, 97,0 y 90,3% para los anti-IFI16 negativos. Los pacientes anti-IFI16 positivos también tenían una supervivencia general menor que los pacientes anti-IFI16 negativos tras ajustar para la presencia o ausencia de ACA mediante análisis multivariado de Cox (hazard ratio [HR]: 3,21; p = 0,043).
Los autoanticuerpos anti-IFI16 se asocian con HAP aislada y una peor supervivencia general. Los autoanticuerpos anti-IFI16 se podrían emplear como marcador suplementario de lcSSc en pacientes SSc seronegativos y para identificar pacientes ACA positivos con un peor pronóstico.
Structural mechanism of dsDNA recognition by the hMNDA HIN domain: New insights into the DNA-binding model of a PYHIN protein
2023, International Journal of Biological Macromolecules
The hematopoietic interferon-inducible nuclear (HIN) domain of the PYHIN family of proteins recognizes double-stranded DNA (dsDNA) through different dsDNA-binding modes. These modes apparently confer different roles upon these proteins in the regulation of innate immune responses, gene transcription, and apoptosis. Myeloid cell nuclear differentiation antigen (MNDA), a member of the human PYHIN family, binds DNA and regulates gene transcription in monocytes. However, the mechanism of DNA recognition and DNA-binding modes of human MNDA (hMNDA) remain unclear. Here, we determined the crystal structure of the hMNDA–HIN domain in complex with dsDNA at 2.4 Å resolution, and reveal that hMNDA–HIN binds to dsDNA in a sequence-independent manner. Structure and mutation studies indicated that hMNDA–HIN binds to dsDNA through a unique mode, involving two dsDNA-binding interfaces. Interface I exhibits an AIM2-like dsDNA-binding mode, and interface II has a previously unreported mode of dsDNA-binding. These results provide new insights into the DNA-binding modes of this PYHIN protein.
PYHIN protein IFI207 regulates cytokine transcription and IRF7 and contributes to the establishment of K. pneumoniae infection
2023, Cell Reports
PYHIN proteins AIM2 and IFI204 sense pathogen DNA, while other PYHINs have been shown to regulate host gene expression through as-yet unclear mechanisms. We characterize mouse PYHIN IFI207, which we find is not involved in DNA sensing but rather is required for cytokine promoter induction in macrophages. IFI207 co-localizes with both active RNA polymerase II (RNA Pol II) and IRF7 in the nucleus and enhances IRF7-dependent gene promoter induction. Generation of Ifi207^−/− mice shows no role for IFI207 in autoimmunity. Rather, IFI207 is required for the establishment of a Klebsiella pneumoniae lung infection and for Klebsiella macrophage phagocytosis. These insights into IFI207 function illustrate that PYHINs can have distinct roles in innate immunity independent of DNA sensing and highlight the need to better characterize the whole mouse locus, one gene at a time.
Targeting the NLRP3 inflammasome in cardiovascular diseases
2022, Pharmacology and Therapeutics
The NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome is an intracellular sensing protein complex that plays a major role in innate immunity. Following tissue injury, activation of the NLRP3 inflammasome results in cytokine production, primarily interleukin(IL)-1β and IL-18, and, eventually, inflammatory cell death – pyroptosis. While a balanced inflammatory response favors damage resolution and tissue healing, excessive NLRP3 activation causes detrimental effects. A key involvement of the NLRP3 inflammasome has been reported across a wide range of cardiovascular diseases (CVDs). Several pharmacological agents selectively targeting the NLRP3 inflammasome system have been developed and tested in animals and early phase human studies with overall promising results. While the NLRP3 inhibitors are in clinical development, multiple randomized trials have demonstrated the safety and efficacy of IL-1 blockade in atherothrombosis, heart failure and recurrent pericarditis. Furthermore, the non-selective NLRP3 inhibitor colchicine has been recently shown to significantly reduce cardiovascular events in patients with chronic coronary disease. In this review, we will outline the mechanisms driving NLRP3 assembly and activation, and discuss the pathogenetic role of the NLRP3 inflammasome in CVDs, providing an overview of the current and future therapeutic approaches targeting the NLRP3 inflammasome.
The significance of interferon gamma inducible protein 16 (IFI16) expression in drug resistant ovarian cancer cell lines
2022, Biomedicine and Pharmacotherapy
Citation Excerpt :
Two HIN domains are separated by serine-threonine-proline (S/T/P)-rich spacer region. The size of the spacer region in the IFI16 protein is regulated by mRNA splicing (Table 1) [21,35,36]. Both nuclear and cytoplasmic localization of IFI16 protein have been described in literature and seems to be regulated by acetylation, phosphorylation and binding with other cellular proteins [28,30].
Inherent or developed during treatment drug resistance is the main reason for the low effectiveness of chemotherapy in ovarian cancer. IFI16 is a cytoplasmic/nuclear protein involved in response to virus’s infection and cell cycle arrest associated with the cellular senescence.
Here we performed a detailed IFI16 expression analysis in ovarian cancer cell lines sensitive (A2780) and resistant to doxorubicin (DOX) (A2780DR1 and A2780DR2) and paclitaxel (PAC) (A2780PR1). IFI16 mRNA level, protein level in the nuclear and cytoplasmic fraction (Western blot analysis), the protein expression in cancer cells and nuclei (immunofluorescence analysis) and cancer patient lesions (immunohistochemistry) were performed in this study.
We observed upregulation of IFI16 expression in drug resistant cell lines with dominant cytoplasmic localization in DOX-resistant cell lines and nuclear one in the PAC-resistant cell line. The most abundantly overexpressed isoforms of IFI16 were IFI16A and IFI16C. Finally, an analysis of a histological type of ovarian cancer (immunohistochemistry) showed expression in serous ovarian cancer.
Expression of IFI16 in drug-resistant cell lines suggests its role in drug resistance development in ovarian cancer. Expression in serous ovarian cancer suggests its role in the pathogenesis of this histological type.

View all citing articles on Scopus

View full text

ReviewThe HIN-200 family: More than interferon-inducible genes?

Abstract

Introduction

Section snippets

Previously identified HIN-200 genes

Protein structure of known and novel proteins

Subcellular localization

Function of HIN-200 proteins

Conclusions and perspectives

Acknowledgments

Molecular biology of the H-2 histocompatibility complex

Science

Interferon action: transcriptional control of a gene specifying a 56,000-Da protein in Ehrlich ascites tumor cells

Virology

Molecular cloning and expression of an interferon-inducible protein encoded by gene 203 from the gene 200 cluster

Eur. J. Biochem.

Interferons as gene activators: close linkage of two interferon-activatable murine genes

Virology

IFN-gamma and IFN-beta independently stimulate the expression of lipopolysaccharide-inducible genes in murine peritoneal macrophages

J. Immunol.

Characteristics of three homologous 202 genes (Ifi202a, Ifi202b, and Ifi202c) from the murine interferon-activatable gene 200 cluster

Genomics

A novel gene constitutively expressed in human lymphoid cells is inducible with interferon-gamma in myeloid cells

Immunogenetics

Nonhistone protein antigen profiles of five leukemic cell lines reflect the extent of myeloid differentiation

Blood

Cloning a novel member of the human interferon-inducible gene family associated with control of tumorigenicity in a model of human melanoma

Oncogene

Isolation and characterization of genes associated with chromosome-6 mediated tumor suppression in human malignant melanoma

Oncogene

Antitumor activity of IFIX, a novel interferon-inducible HIN-200 gene, in breast cancer

Oncogene

The human myeloid cell nuclear differentiation antigen gene is one of at least two related interferon-inducible genes located on chromosome 1q that are expressed specifically in hematopoietic cells

Blood

Interferons as gene activators: a cluster of six interferon-activatable genes is linked to the erythroid alpha-spectrin locus on murine chromosome 1

Virology

Human genome: end of the beginning

Nature

The interferon-inducible p200 family of proteins: a perspective on their roles in cell cycle regulation and differentiation

Blood Cells Mol. Dis.

The mouse Ifi200 gene cluster: genomic sequence, analysis, and comparison with the human HIN-200 gene cluster

Genomics

Genomic anatomy of a premier major histocompatibility complex paralogous region on chromosome 1q21–q22

Genome Res.

p202 self-associates through a sequence conserved among the members of the 200-family proteins

FEBS Lett.

Binding of an interferon-inducible protein (p202) to the retinoblastoma protein

J. Biol. Chem.

Comparative analysis of apoptosis and inflammation genes of mice and humans

Genome Res.

PAAD—A new protein domain associated with apoptosis, cancer and autoimmune diseases

Trends Biochem. Sci.

The DAPIN family: a novel domain links apoptotic and interferon response proteins

Trends Biochem. Sci.

Isotypic variants of the interferon-inducible transcriptional repressor IFI 16 arise through differential mRNA splicing

Biochemistry

MNDA dimerizes through a complex motif involving an N-terminal basic region

FEBS Lett.

Biochemical and growth regulatory activities of the HIN-200 family member and putative tumor suppressor protein, AIM2

Biochem. Biophys. Res. Commun.

The interferon-inducible autoantigen, IFI 16: localization to the nucleolus and identification of a DNA-binding domain

Biochem. Biophys. Res. Commun.

Homology modeling provides insights into the binding mode of the PAAD/DAPIN/pyrin domain, a fourth member of the CARD/DD/DED domain family

Protein Sci.

The interferon-inducible growth-inhibitory p202 protein: DNA binding properties and identification of a DNA binding domain

Biochem. Biophys. Res. Commun.

The HIN domain of IFI-200 proteins consists of two OB folds

Biochem. Biophys. Res. Commun.

p202, an interferon-inducible modulator of transcription, inhibits transcriptional activation by the p53 tumor suppressor protein, and a segment from the p53-binding protein 1 that binds to p202 overcomes this inhibition

J. Biol. Chem.

The human interferon-inducible protein, IFI 16, is a repressor of transcription

J. Biol. Chem.

Functional interaction between p53 and the interferon-inducible nucleoprotein IFI 16

Oncogene

The interferon-inducible p202a protein modulates NF-kappaB activity by inhibiting the binding to DNA of p50/p65 heterodimers and p65 homodimers while enhancing the binding of p50 homodimers

J. Biol. Chem.

The Ifi 200 genes: an emerging family of IFN-inducible genes

Biochimie

Inhibition of growth by p205: a nuclear protein and putative tumor suppressor expressed during myeloid cell differentiation

Stem Cells

Review
The HIN-200 family: More than interferon-inducible genes?