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Article ; Online: Regulation of the bi-directional cross-talk between ovarian cancer cells and adipocytes by SPARC.

John, Bincy / Naczki, Christine / Patel, Chirayu / Ghoneum, Alia / Qasem, Shadi / Salih, Ziyan / Said, Neveen

2019 Volume 38, Issue 22, Page(s) 4366–4383

Abstract: Ovarian cancer (OvCa) exhibits a specific predilection for metastasis to the omentum. Our earlier studies highlighted the tumour-suppressor effect of secreted protein acidic and rich in cysteine (SPARC) in OvCa through multi-faceted roles inhibiting ... ...

Abstract	Ovarian cancer (OvCa) exhibits a specific predilection for metastasis to the omentum. Our earlier studies highlighted the tumour-suppressor effect of secreted protein acidic and rich in cysteine (SPARC) in OvCa through multi-faceted roles inhibiting cancer cell interactions within the peritoneal milieu. The goal of this study is to investigate the role of SPARC in OvCa interactions with omental adipocytes and its role in OvCa colonization in the omentum. We employed multi-pronged approach using primary omental adipocytes from Sparc knockout mice, genetically engineered human omental adipocytes in 3D co-cultures with OvCa cells, as well as treatment with recombinant SPARC protein. We show that SPARC suppresses multistep cascade in OvCa omental metastasis. SPARC inhibited in vivo and adipocyte-induced homing, proliferation, and invasion of OvCa cells. SPARC suppressed metabolic programming of both adipocytes and OvCa cells and exerted an inhibitory effect of adipocyte differentiation and their phenotypic switch to cancer-associated phenotype. Mechanistic studies revealed that this effect is mediated through inhibition of cEBPβ-NFkB-AP-1 transcription machinery. These findings define a novel and functionally important role of SPARC in OvCa and not only bridge the knowledge gap but highlight the need to consider SPARC protein expression in therapeutic development.
MeSH term(s)	Adipocytes/metabolism ; Adipocytes/pathology ; Animals ; Cell Differentiation/physiology ; Cell Line, Tumor ; Cell Proliferation/physiology ; Coculture Techniques/methods ; Female ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplasm Invasiveness/pathology ; Omentum/metabolism ; Omentum/pathology ; Osteonectin/metabolism ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Ovary/metabolism ; Ovary/pathology ; Transcription, Genetic/physiology
Chemical Substances	Osteonectin
Language	English
Publishing date	2019-02-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-019-0728-3
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Article: SPARC Inhibits Metabolic Plasticity in Ovarian Cancer.

Naczki, Christine / John, Bincy / Patel, Chirayu / Lafferty, Ashlyn / Ghoneum, Alia / Afify, Hesham / White, Michael / Davis, Amanda / Jin, Guangxu / Kridel, Steven / Said, Neveen

Cancers

2018 Volume 10, Issue 10

Abstract: The tropism of ovarian cancer (OvCa) to the peritoneal cavity is implicated in widespread dissemination, suboptimal surgery, and poor prognosis. This tropism is influenced by stromal factors that are not only critical for the oncogenic and metastatic ... ...

Abstract	The tropism of ovarian cancer (OvCa) to the peritoneal cavity is implicated in widespread dissemination, suboptimal surgery, and poor prognosis. This tropism is influenced by stromal factors that are not only critical for the oncogenic and metastatic cascades, but also in the modulation of cancer cell metabolic plasticity to fulfill their high energy demands. In this respect, we investigated the role of Secreted Protein Acidic and Rich in Cysteine (SPARC) in metabolic plasticity of OvCa. We used a syngeneic model of OvCa in
Language	English
Publishing date	2018-10-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers10100385
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Article ; Online: Tumor-induced loss of mural Connexin 43 gap junction activity promotes endothelial proliferation.

Choudhary, Mayur / Naczki, Christine / Chen, Wenhong / Barlow, Keith D / Case, L Douglas / Metheny-Barlow, Linda J

BMC cancer

2015 Volume 15, Page(s) 427

Abstract: Background: Proper functional association between mural cells and endothelial cells (EC) causes EC of blood vessels to become quiescent. Mural cells on tumor vessels exhibit decreased attachment to EC, which allows vessels to be unstable and ... ...

Abstract	Background: Proper functional association between mural cells and endothelial cells (EC) causes EC of blood vessels to become quiescent. Mural cells on tumor vessels exhibit decreased attachment to EC, which allows vessels to be unstable and proliferative. The mechanisms by which tumors prevent proper association between mural cells and EC are not well understood. Since gap junctions (GJ) play an important role in cell-cell contact and communication, we investigated whether loss of GJ plays a role in tumor-induced mural cell dissociation. Methods: Mural cell regulation of endothelial proliferation was assessed by direct co-culture assays of fluorescently labeled cells quantified by flow cytometry or plate reader. Gap junction function was assessed by parachute assay. Connexin 43 (Cx43) protein in mural cells exposed to conditioned media from cancer cells was assessed by Western and confocal microscopy; mRNA levels were assessed by quantitative real-time PCR. Expression vectors or siRNA were utilized to overexpress or knock down Cx43. Tumor growth and angiogenesis was assessed in mouse hosts deficient for Cx43. Results: Using parachute dye transfer assay, we demonstrate that media conditioned by MDA-MB-231 breast cancer cells diminishes GJ communication between mural cells (vascular smooth muscle cells, vSMC) and EC. Both protein and mRNA of the GJ component Connexin 43 (Cx43) are downregulated in mural cells by tumor-conditioned media; media from non-tumorigenic MCF10A cells had no effect. Loss of GJ communication by Cx43 siRNA knockdown, treatment with blocking peptide, or exposure to tumor-conditioned media diminishes the ability of mural cells to inhibit EC proliferation in co-culture assays, while overexpression of Cx43 in vSMC restores GJ and endothelial inhibition. Breast tumor cells implanted into mice heterozygous for Cx43 show no changes in tumor growth, but exhibit significantly increased tumor vascularization determined by CD31 staining, along with decreased mural cell support detected by NG2 staining. Conclusions: Our data indicate that i) functional Cx43 is required for mural cell-induced endothelial quiescence, and ii) downregulation of Cx43 GJ by tumors frees endothelium to respond to angiogenic cues. These data define a novel and important role for maintained Cx43 function in regulation of vessel quiescence, and suggest its loss may contribute to pathological tumor angiogenesis.
MeSH term(s)	Animals ; Breast Neoplasms/blood supply ; Breast Neoplasms/metabolism ; Cell Communication ; Cell Line, Tumor ; Cell Proliferation ; Connexin 43/antagonists & inhibitors ; Connexin 43/genetics ; Connexin 43/metabolism ; Culture Media, Conditioned ; Endothelial Cells/physiology ; Endothelium, Vascular/physiopathology ; Gap Junctions/metabolism ; Humans ; Mice ; Myocytes, Smooth Muscle/metabolism ; Neovascularization, Pathologic/physiopathology ; RNA, Messenger/metabolism
Chemical Substances	Connexin 43 ; Culture Media, Conditioned ; GJA1 protein, human ; RNA, Messenger
Language	English
Publishing date	2015-05-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1471-2407
ISSN (online)	1471-2407
DOI	10.1186/s12885-015-1420-9
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Article: Replication and cytopathic effect of oncolytic vesicular stomatitis virus in hypoxic tumor cells in vitro and in vivo.

Connor, John H / Naczki, Christine / Koumenis, Costas / Lyles, Douglas S

Journal of virology

2004 Volume 78, Issue 17, Page(s) 8960–8970

Abstract: Tumor hypoxia presents an obstacle to the effectiveness of most antitumor therapies, including treatment with oncolytic viruses. In particular, an oncolytic virus must be resistant to the inhibition of DNA, RNA, and protein synthesis that occurs during ... ...

Abstract	Tumor hypoxia presents an obstacle to the effectiveness of most antitumor therapies, including treatment with oncolytic viruses. In particular, an oncolytic virus must be resistant to the inhibition of DNA, RNA, and protein synthesis that occurs during hypoxic stress. Here we show that vesicular stomatitis virus (VSV), an oncolytic RNA virus, is capable of replication under hypoxic conditions. In cells undergoing hypoxic stress, VSV infection produced larger amounts of mRNA than under normoxic conditions. However, translation of these mRNAs was reduced at earlier times postinfection in hypoxia-adapted cells than in normoxic cells. At later times postinfection, VSV overcame a hypoxia-associated increase in alpha subunit of eukaryotic initiation factor 2 (eIF-2alpha) phosphorylation and initial suppression of viral protein synthesis in hypoxic cells to produce large amounts of viral protein. VSV infection caused the dephosphorylation of the translation initiation factor eIF-4E and inhibited host translation similarly under both normoxic and hypoxic conditions. VSV produced progeny virus to similar levels in hypoxic and normoxic cells and showed the ability to expand from an initial infection of 1% of hypoxic cells to spread through an entire population. In all cases, virus infection induced classical cytopathic effects and apoptotic cell death. When VSV was used to treat tumors established in nude mice, we found VSV replication in hypoxic areas of these tumors. This occurred whether the virus was administered intratumorally or intravenously. These results show for the first time that VSV has an inherent capacity for infecting and killing hypoxic cancer cells. This ability could represent a critical advantage over existing therapies in treating established tumors.
MeSH term(s)	Animals ; Apoptosis ; Cell Hypoxia ; Cytopathogenic Effect, Viral/physiology ; Eukaryotic Initiation Factors/metabolism ; HeLa Cells ; Humans ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Neoplasms/pathology ; Neoplasms/therapy ; Neoplasms/virology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Viral/genetics ; RNA, Viral/metabolism ; Transplantation, Heterologous ; Vesicular stomatitis Indiana virus/genetics ; Vesicular stomatitis Indiana virus/pathogenicity ; Vesicular stomatitis Indiana virus/physiology ; Virus Replication/physiology
Chemical Substances	Eukaryotic Initiation Factors ; RNA, Messenger ; RNA, Viral
Language	English
Publishing date	2004-09
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.78.17.8960-8970.2004
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Article ; Online: 19-nor-1 alpha,25-dihydroxyvitamin D2 (paricalcitol) inhibits the proliferation of human pancreatic cancer cells in vitro and in vivo.

Schwartz, Gary G / Eads, Dawn / Naczki, Christine / Northrup, Scott / Chen, Tai / Koumenis, Constantinos

Cancer biology & therapy

2007 Volume 7, Issue 3, Page(s) 430–436

Abstract: 1,25-dihydroxyvitamin D(3), (1,25(OH)(2)D(3); calcitriol), the hormonal form of vitamin D, exerts growth-inhibitory, pro-apoptotic and anti-metastatic effects on tumor cells in vitro and in vivo but its clinical use is limited by its calcemic effects. ... ...

Abstract	1,25-dihydroxyvitamin D(3), (1,25(OH)(2)D(3); calcitriol), the hormonal form of vitamin D, exerts growth-inhibitory, pro-apoptotic and anti-metastatic effects on tumor cells in vitro and in vivo but its clinical use is limited by its calcemic effects. Previous studies have shown that the antiproliferative effects of the less calcemic calcitriol analog 19-nor-1,25-(OH)(2)D(2) (paricalcitol) on prostate tumor cell lines are indistinguishable from those of 1,25(OH)(2)D(3). We therefore investigated the anti-proliferative effects of paricalcitol on the growth of pancreatic tumor cell lines in vitro and in vivo. Both 1,25(OH)(2)D(3) and paricalcitol inhibited the growth of BxPC-3, Hs700T and AsPC-1 lines in a dose-dependent manner. This antiproliferative activity correlated with upregulation of the cell cycle inhibitors p21 (Waf1/CIP1) and p27(Kip1). A fourth pancreatic cell line, Hs766T was unresponsive to both paricalcitol and calcitriol. Hs766T cells also failed to upregulate p21/Waf-1/Cip1 or p27/KiP in response to treatments with these agents. Paricalcitol, given three times per week inhibited the growth of AsPC-1 pancreatic tumor cell xenografts in nude mice at a dose that did not cause hypercalcaemia. Tumor inhibition was accompanied by in vivo upregulation of p21 and p27 expression. Given the few therapeutic options for patients with pancreatic cancer, further exploration of paricalcitol, an FDA-approved medication, is warranted.
MeSH term(s)	Bone Density Conservation Agents/pharmacology ; Cell Division/drug effects ; Cell Line, Tumor ; Ergocalciferols/chemistry ; Ergocalciferols/pharmacology ; Humans ; Models, Molecular ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/pathology
Chemical Substances	Bone Density Conservation Agents ; Ergocalciferols ; paricalcitol (6702D36OG5)
Language	English
Publishing date	2007-12-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2146305-0
ISSN	1555-8576 ; 1538-4047
ISSN (online)	1555-8576
ISSN	1538-4047
DOI	10.4161/cbt.7.3.5418
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Zs.A 5887: Show issues

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Article: Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha.

Koumenis, Constantinos / Naczki, Christine / Koritzinsky, Marianne / Rastani, Sally / Diehl, Alan / Sonenberg, Nahum / Koromilas, Antonis / Wouters, Bradly G

Molecular and cellular biology

2002 Volume 22, Issue 21, Page(s) 7405–7416

Abstract: Hypoxia profoundly influences tumor development and response to therapy. While progress has been made in identifying individual gene products whose synthesis is altered under hypoxia, little is known about the mechanism by which hypoxia induces a global ... ...

Abstract	Hypoxia profoundly influences tumor development and response to therapy. While progress has been made in identifying individual gene products whose synthesis is altered under hypoxia, little is known about the mechanism by which hypoxia induces a global downregulation of protein synthesis. A critical step in the regulation of protein synthesis in response to stress is the phosphorylation of translation initiation factor eIF2alpha on Ser51, which leads to inhibition of new protein synthesis. Here we report that exposure of human diploid fibroblasts and transformed cells to hypoxia led to phosphorylation of eIF2alpha, a modification that was readily reversed upon reoxygenation. Expression of a transdominant, nonphosphorylatable mutant allele of eIF2alpha attenuated the repression of protein synthesis under hypoxia. The endoplasmic reticulum (ER)-resident eIF2alpha kinase PERK was hyperphosphorylated upon hypoxic stress, and overexpression of wild-type PERK increased the levels of hypoxia-induced phosphorylation of eIF2alpha. Cells stably expressing a dominant-negative PERK allele and mouse embryonic fibroblasts with a homozygous deletion of PERK exhibited attenuated phosphorylation of eIF2alpha and reduced inhibition of protein synthesis in response to hypoxia. PERK(-/-) mouse embryo fibroblasts failed to phosphorylate eIF2alpha and exhibited lower survival after prolonged exposure to hypoxia than did wild-type fibroblasts. These results indicate that adaptation of cells to hypoxic stress requires activation of PERK and phosphorylation of eIF2alpha and suggest that the mechanism of hypoxia-induced translational attenuation may be linked to ER stress and the unfolded-protein response.
MeSH term(s)	3T3 Cells ; Animals ; Cobalt/pharmacology ; Endoplasmic Reticulum/enzymology ; Enzyme Activation ; Eukaryotic Initiation Factor-2/metabolism ; Fibroblasts/metabolism ; Gene Deletion ; Genes, Dominant ; HeLa Cells ; Homozygote ; Humans ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit ; Immunoblotting ; Kinetics ; Methionine/metabolism ; Mice ; Models, Biological ; Oxygen/metabolism ; Phosphorylation ; Plasmids/metabolism ; Protein Biosynthesis ; Protein Folding ; Proteins/metabolism ; Serine/chemistry ; Thapsigargin/pharmacology ; Time Factors ; Transcription Factors/metabolism ; Transfection ; eIF-2 Kinase/metabolism
Chemical Substances	Eukaryotic Initiation Factor-2 ; HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; Proteins ; Transcription Factors ; Cobalt (3G0H8C9362) ; Serine (452VLY9402) ; Thapsigargin (67526-95-8) ; Methionine (AE28F7PNPL) ; PERK kinase (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1) ; cobaltous chloride (EVS87XF13W) ; Oxygen (S88TT14065)
Language	English
Publishing date	2002-09-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.22.21.7405-7416.2002
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Article: The adenovirus E4orf6 protein inhibits DNA double strand break repair and radiosensitizes human tumor cells in an E1B-55K-independent manner.

Hart, Lori S / Yannone, Steven M / Naczki, Christine / Orlando, Joseph S / Waters, Stephen B / Akman, Steven A / Chen, David J / Ornelles, David / Koumenis, Constantinos

The Journal of biological chemistry

2004 Volume 280, Issue 2, Page(s) 1474–1481

Abstract: The adenoviral protein E4orf6 has been shown to inhibit both in vitro V(D)J recombination and adenoviral DNA concatenation, two processes that rely on cellular DNA double strand break repair (DSBR) proteins. Most of the known activities of E4orf6 during ... ...

Abstract	The adenoviral protein E4orf6 has been shown to inhibit both in vitro V(D)J recombination and adenoviral DNA concatenation, two processes that rely on cellular DNA double strand break repair (DSBR) proteins. Most of the known activities of E4orf6 during adenoviral infection require its interaction with another adenoviral protein, E1B-55K. Here we report that E4orf6, stably expressed in RKO human colorectal carcinoma cells or transiently expressed by adenoviral vector in U251 human glioblastoma cells, inhibits DSBR and induces significant radiosensitization in the absence of E1B-55K. Expression of a mutant form of E4orf6 (L245P) failed to radiosensitize RKO cells. E4orf6 reduced DSBR capacity in transfected and infected cells, as measured by sublethal DNA damage repair assay and phosphorylated H2AX (gamma-H2AX) levels, respectively. Consistent with the inhibitory effect of E4orf6 on DSBR, expression of wild-type but not mutant E4orf6 reduced recovery of a transfected, replicating reporter plasmid (pSP189) in 293 cells but did not increase the mutation frequency measured in the reporter plasmid. The kinase activity of DNA-PKcs (the DNA-dependent protein kinase catalytic subunit) toward heterologous substrates was not affected by expression of E4orf6; however, autophosphorylation of DNA-PKcs at Thr-2609 following ionizing radiation was prolonged in the presence of E4orf6 when compared with control-infected cells. Our results demonstrate for the first time that E4orf6 expression hinders the cellular DNA repair process in mammalian cells in the absence of E1B-55K or other adenoviral genes and suggest that viral-mediated delivery of E4orf6, combined with localized external beam radiation, could be a useful approach for the treatment of radioresistant solid tumors such as glioblastomas.
MeSH term(s)	Adenoviridae/genetics ; Adenoviridae/physiology ; Adenovirus E1B Proteins/metabolism ; Adenovirus E4 Proteins/genetics ; Adenovirus E4 Proteins/metabolism ; Cell Line, Tumor ; DNA Damage/radiation effects ; DNA Repair ; DNA-Activated Protein Kinase ; DNA-Binding Proteins/metabolism ; Humans ; Models, Biological ; Mutation/genetics ; Nuclear Proteins ; Open Reading Frames/genetics ; Phosphorylation ; Protein-Serine-Threonine Kinases/metabolism ; Radiation Tolerance ; Radiation, Ionizing ; Threonine/genetics ; Threonine/metabolism ; Transduction, Genetic
Chemical Substances	Adenovirus E1B Proteins ; Adenovirus E4 Proteins ; DNA-Binding Proteins ; Nuclear Proteins ; Threonine (2ZD004190S) ; DNA-Activated Protein Kinase (EC 2.7.11.1) ; PRKDC protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2004-10-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M409934200
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Article: ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth.

Bi, Meixia / Naczki, Christine / Koritzinsky, Marianne / Fels, Diane / Blais, Jaime / Hu, Nianping / Harding, Heather / Novoa, Isabelle / Varia, Mahesh / Raleigh, James / Scheuner, Donalyn / Kaufman, Randal J / Bell, John / Ron, David / Wouters, Bradly G / Koumenis, Constantinos

The EMBO journal

2005 Volume 24, Issue 19, Page(s) 3470–3481

Abstract: Tumor cell adaptation to hypoxic stress is an important determinant of malignant progression. While much emphasis has been placed on the role of HIF-1 in this context, the role of additional mechanisms has not been adequately explored. Here we ... ...

Abstract	Tumor cell adaptation to hypoxic stress is an important determinant of malignant progression. While much emphasis has been placed on the role of HIF-1 in this context, the role of additional mechanisms has not been adequately explored. Here we demonstrate that cells cultured under hypoxic/anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR), which adapts cells to endoplasmic reticulum (ER) stress. Inactivation of ISR signaling by mutations in the ER kinase PERK and the translation initiation factor eIF2alpha or by a dominant-negative PERK impairs cell survival under extreme hypoxia. Tumors derived from these mutant cell lines are smaller and exhibit higher levels of apoptosis in hypoxic areas compared to tumors with an intact ISR. Moreover, expression of the ISR targets ATF4 and CHOP was noted in hypoxic areas of human tumor biopsy samples. Collectively, these findings demonstrate that activation of the ISR is required for tumor cell adaptation to hypoxia, and suggest that this pathway is an attractive target for antitumor modalities.
MeSH term(s)	Activating Transcription Factor 4/metabolism ; Animals ; Apoptosis/genetics ; Apoptosis/physiology ; Cell Line, Tumor ; Cell Survival/genetics ; Cell Survival/physiology ; Endoplasmic Reticulum/physiology ; Eukaryotic Initiation Factor-2/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Hypoxia/physiopathology ; Immunohistochemistry ; Mice ; Mice, Nude ; Mutation/genetics ; Neoplasms/metabolism ; Neoplasms/physiopathology ; Signal Transduction/genetics ; Signal Transduction/physiology ; Stress, Physiological/metabolism ; Stress, Physiological/physiopathology ; Transcription Factor CHOP/metabolism ; eIF-2 Kinase/genetics ; eIF-2 Kinase/metabolism
Chemical Substances	ATF4 protein, human ; DDIT3 protein, human ; Eukaryotic Initiation Factor-2 ; Activating Transcription Factor 4 (145891-90-3) ; Transcription Factor CHOP (147336-12-7) ; PERK kinase (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2005-10-05
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.1038/sj.emboj.7600777
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