Laxminarayana R. Devireddy, Jose G. Teodoro, Fabien A. Richard, Michael R. Green^*

Many hematopoietic cells undergo apoptosis when deprived of specific cytokines, and this process requires de novo RNA/protein synthesis. Using DNA microarrays to analyze interleukin-3 (IL-3)-dependent murine FL5.12 pro-B cells, we found that the gene undergoing maximal transcriptional induction after cytokine withdrawal is 24p3, which encodes a secreted lipocalin. Conditioned medium from IL-3-deprived FL5.12 cells contained 24p3 and induced apoptosis in naïve FL5.12 cells even when IL-3 was present. 24p3 also induced apoptosis in a wide variety of leukocytes but not other cell types. Apoptotic sensitivity correlated with the presence of a putative 24p3 cell surface receptor. We conclude that IL-3 deprivation activates 24p3 transcription, leading to synthesis and secretion of 24p3, which induces apoptosis through an autocrine pathway.

Howard Hughes Medical Institute, Program in Gene Function and Expression and Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
^*   To whom correspondence should be addressed. E-mail: michael.green{at}umassmed.edu

Impaired Neutrophil Function in 24p3 Null Mice Contributes to Enhanced Susceptibility to Bacterial Infections.

Z. Liu, R. Petersen, and L. Devireddy (2013)
J. Immunol. 190, 4692-4706
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Reactive astrocytes secrete lcn2 to promote neuron death.

F. Bi, C. Huang, J. Tong, G. Qiu, B. Huang, Q. Wu, F. Li, Z. Xu, R. Bowser, X.-G. Xia, et al. (2013)
PNAS 110, 4069-4074
 |  Abstract »  |  Full Text »  |  PDF »

Transcription factor ATF5 is required for terminal differentiation and survival of olfactory sensory neurons.

S.-Z. Wang, J. Ou, L. J. Zhu, and M. R. Green (2012)
PNAS 109, 18589-18594
 |  Abstract »  |  Full Text »  |  PDF »

Interleukin-10-Induced Neutrophil Gelatinase-Associated Lipocalin Production in Macrophages with Consequences for Tumor Growth.

M. Jung, A. Weigert, M. Tausendschon, J. Mora, B. Oren, A. Sola, G. Hotter, T. Muta, and B. Brune (2012)
Mol. Cell. Biol. 32, 3938-3948
 |  Abstract »  |  Full Text »  |  PDF »

Mammalian Siderophores, Siderophore-binding Lipocalins, and the Labile Iron Pool.

C. Correnti and R. K. Strong (2012)
J. Biol. Chem. 287, 13524-13531
 |  Abstract »  |  Full Text »  |  PDF »

Lipocalin-2 Induces Cardiomyocyte Apoptosis by Increasing Intracellular Iron Accumulation.

G. Xu, J. Ahn, S. Chang, M. Eguchi, A. Ogier, S. Han, Y. Park, C. Shim, Y. Jang, B. Yang, et al. (2012)
J. Biol. Chem. 287, 4808-4817
 |  Abstract »  |  Full Text »  |  PDF »

Lipocalin-2 (24p3/Neutrophil Gelatinase-associated Lipocalin (NGAL)) Receptor Is Expressed in Distal Nephron and Mediates Protein Endocytosis.

C. Langelueddecke, E. Roussa, R. A. Fenton, N. A. Wolff, W.-K. Lee, and F. Thevenod (2012)
J. Biol. Chem. 287, 159-169
 |  Abstract »  |  Full Text »  |  PDF »

Upregulation of Inflammatory Mediators in End-Stage Renal Disease as Measured Using Biochip Array Technology.

R. Davis, V. Bansal, E. Litinas, D. Hoppensteadt, I. Thethi, K. Nelson, and J. Fareed (2011)
Clinical and Applied Thrombosis/Hemostasis 17, E218-E223
 |  Abstract »  |  PDF »

BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription.

Z. Sheng, L. Ma, J. E. Sun, L. J. Zhu, and M. R. Green (2011)
Blood 118, 2840-2848
 |  Abstract »  |  Full Text »  |  PDF »

Multiple Apoptotic Defects in Hematopoietic Cells from Mice Lacking Lipocalin 24p3.

Z. Liu, A. Yang, Z. Wang, K. D. Bunting, G. Davuluri, M. R. Green, and L. R. Devireddy (2011)
J. Biol. Chem. 286, 20606-20614
 |  Abstract »  |  Full Text »  |  PDF »

Expanding the adipokine network in cartilage: identification and regulation of novel factors in human and murine chondrocytes.

J. Conde, R. Gomez, G. Bianco, M. Scotece, P. Lear, C. Dieguez, J. Gomez-Reino, F. Lago, and O. Gualillo (2011)
Ann Rheum Dis 70, 551-559
 |  Abstract »  |  Full Text »  |  PDF »

Lipocalin 2 is a selective modulator of peroxisome proliferator-activated receptor-{gamma} activation and function in lipid homeostasis and energy expenditure.

D. Jin, H. Guo, S. Y. Bu, Y. Zhang, J. Hannaford, D. G. Mashek, and X. Chen (2011)
FASEB J 25, 754-764
 |  Abstract »  |  Full Text »  |  PDF »

Lipocalin-2 Deficiency Impairs Thermogenesis and Potentiates Diet-Induced Insulin Resistance in Mice.

H. Guo, D. Jin, Y. Zhang, W. Wright, M. Bazuine, D. A. Brockman, D. A. Bernlohr, and X. Chen (2010)
Diabetes 59, 1376-1385
 |  Abstract »  |  Full Text »  |  PDF »

FOXO3a Regulates Glycolysis via Transcriptional Control of Tumor Suppressor TSC1.

S. Khatri, H. Yepiskoposyan, C. A. Gallo, P. Tandon, and D. R. Plas (2010)
J. Biol. Chem. 285, 15960-15965
 |  Abstract »  |  Full Text »  |  PDF »

Neutrophil Gelatinase-Associated Lipocalin Expresses Antimicrobial Activity by Interfering with L-Norepinephrine-Mediated Bacterial Iron Acquisition.

M. Miethke and A. Skerra (2010)
Antimicrob. Agents Chemother. 54, 1580-1589
 |  Abstract »  |  Full Text »  |  PDF »

Upregulation of Neutrophil Gelatinase-Associated Lipocalin by ErbB2 through Nuclear Factor-{kappa}B Activation.

S.-H. Li, V. S. Hawthorne, C. L. Neal, S. Sanghera, J. Xu, J. Yang, H. Guo, P. S. Steeg, and D. Yu (2009)
Cancer Res. 69, 9163-9168
 |  Abstract »  |  Full Text »  |  PDF »

Inhibition of Lipocalin 2 Impairs Breast Tumorigenesis and Metastasis.

X. Leng, T. Ding, H. Lin, Y. Wang, L. Hu, J. Hu, B. Feig, W. Zhang, L. Pusztai, W. F. Symmans, et al. (2009)
Cancer Res. 69, 8579-8584
 |  Abstract »  |  Full Text »  |  PDF »

Lipocalin 2 Expressions Correlate Significantly With Tumor Differentiation in Epithelial Ovarian Cancer.

H. Cho and J.-H. Kim (2009)
Journal of Histochemistry & Cytochemistry 57, 513-521
 |  Abstract »  |  Full Text »  |  PDF »

Lipocalin 2 promotes breast cancer progression.

J. Yang, D. R. Bielenberg, S. J. Rodig, R. Doiron, M. C. Clifton, A. L. Kung, R. K. Strong, D. Zurakowski, and M. A. Moses (2009)
PNAS 106, 3913-3918
 |  Abstract »  |  Full Text »  |  PDF »

Identification of 24p3 as a Direct Target of Foxo3a Regulated by Interleukin-3 through the Phosphoinositide 3-Kinase/Akt Pathway.

S. Park, J. Guo, D. Kim, and J. Q. Cheng (2009)
J. Biol. Chem. 284, 2187-2193
 |  Abstract »  |  Full Text »  |  PDF »

Lipocalin-2 Is an Autocrine Mediator of Reactive Astrocytosis.

S. Lee, J.-Y. Park, W.-H. Lee, H. Kim, H.-C. Park, K. Mori, and K. Suk (2009)
J. Neurosci. 29, 234-249
 |  Abstract »  |  Full Text »  |  PDF »

Lipocalin 2-Dependent Inhibition of Mycobacterial Growth in Alveolar Epithelium.

H. Saiga, J. Nishimura, H. Kuwata, M. Okuyama, S. Matsumoto, S. Sato, M. Matsumoto, S. Akira, Y. Yoshikai, K. Honda, et al. (2008)
J. Immunol. 181, 8521-8527
 |  Abstract »  |  Full Text »  |  PDF »

The Role of Lipocalin 2 in the Regulation of Inflammation in Adipocytes and Macrophages.

J. Zhang, Y. Wu, Y. Zhang, D. LeRoith, D. A. Bernlohr, and X. Chen (2008)
Mol. Endocrinol. 22, 1416-1426
 |  Abstract »  |  Full Text »  |  PDF »

CCAAT/enhancer binding protein {beta} deficiency provides cerebral protection following excitotoxic injury.

M. Cortes-Canteli, R. Luna-Medina, M. Sanz-SanCristobal, A. Alvarez-Barrientos, A. Santos, and A. Perez-Castillo (2008)
J. Cell Sci. 121, 1224-1234
 |  Abstract »  |  Full Text »  |  PDF »

Stress-induced Translation of ATF5 mRNA Is Regulated by the 5'-Untranslated Region.

Y. Watatani, K. Ichikawa, N. Nakanishi, M. Fujimoto, H. Takeda, N. Kimura, H. Hirose, S. Takahashi, and Y. Takahashi (2008)
J. Biol. Chem. 283, 2543-2553
 |  Abstract »  |  Full Text »  |  PDF »

The Adipokine Lipocalin 2 Is Regulated by Obesity and Promotes Insulin Resistance.

Q.-W. Yan, Q. Yang, N. Mody, T. E. Graham, C.-H. Hsu, Z. Xu, N. E. Houstis, B. B. Kahn, and E. D. Rosen (2007)
Diabetes 56, 2533-2540
 |  Abstract »  |  Full Text »  |  PDF »

Siderophore-Based Iron Acquisition and Pathogen Control.

M. Miethke and M. A. Marahiel (2007)
Microbiol. Mol. Biol. Rev. 71, 413-451
 |  Abstract »  |  Full Text »  |  PDF »

A Dual Role of Lipocalin 2 in the Apoptosis and Deramification of Activated Microglia.

S. Lee, J. Lee, S. Kim, J.-Y. Park, W.-H. Lee, K. Mori, S.-H. Kim, I. K. Kim, and K. Suk (2007)
J. Immunol. 179, 3231-3241
 |  Abstract »  |  Full Text »  |  PDF »

Survival Factor Withdrawal-induced Apoptosis of TF-1 Cells Involves a TRB2-Mcl-1 Axis-dependent Pathway.

K.-R. Lin, S.-F. Lee, C.-M. Hung, C.-L. Li, H.-F. Yang-Yen, and J. J. Y. Yen (2007)
J. Biol. Chem. 282, 21962-21972
 |  Abstract »  |  Full Text »  |  PDF »

Repression of IFN Regulatory Factor 8 by DNA Methylation Is a Molecular Determinant of Apoptotic Resistance and Metastatic Phenotype in Metastatic Tumor Cells.

D. Yang, M. Thangaraju, K. Greeneltch, D. D. Browning, P. V. Schoenlein, T. Tamura, K. Ozato, V. Ganapathy, S. I. Abrams, and K. Liu (2007)
Cancer Res. 67, 3301-3309
 |  Abstract »  |  Full Text »  |  PDF »

Lipocalin-2 Is an Inflammatory Marker Closely Associated with Obesity, Insulin Resistance, and Hyperglycemia in Humans.

Y. Wang, K. S. L. Lam, E. W. Kraegen, G. Sweeney, J. Zhang, A. W.K. Tso, W.-S. Chow, N. M.S. Wat, J. Y. Xu, R. L.C. Hoo, et al. (2007)
Clin. Chem. 53, 34-41
 |  Abstract »  |  Full Text »  |  PDF »

The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2.

M. A. Fischbach, H. Lin, L. Zhou, Y. Yu, R. J. Abergel, D. R. Liu, K. N. Raymond, B. L. Wanner, R. K. Strong, C. T. Walsh, et al. (2006)
PNAS 103, 16502-16507
 |  Abstract »  |  Full Text »  |  PDF »

Internalization and trafficking of mouse 24p3 protein in L929 cells.

H.-Y. Chou, N. Elangovan, Y.-C. Lee, H. H. Lin, and S.-T. Chu (2006)
J. Endocrinol. 191, 239-247
 |  Abstract »  |  Full Text »  |  PDF »

Identification of Common Transcriptional Regulatory Elements in Interleukin-17 Target Genes.

F. Shen, Z. Hu, J. Goswami, and S. L. Gaffen (2006)
J. Biol. Chem. 281, 24138-24148
 |  Abstract »  |  Full Text »  |  PDF »

Spermatogonial Cell-Mediated Activation of an I{kappa}B{zeta}-Independent Nuclear Factor-{kappa}B Pathway in Sertoli Cells Induces Transcription of the Lipocalin-2 Gene.

R.-S. Fujino, K. Tanaka, M. Morimatsu, K. Tamura, H. Kogo, and T. Hara (2006)
Mol. Endocrinol. 20, 904-915
 |  Abstract »  |  Full Text »  |  PDF »

Lipocalin 2-deficient mice exhibit increased sensitivity to Escherichia coli infection but not to ischemia-reperfusion injury.

T. Berger, A. Togawa, G. S. Duncan, A. J. Elia, A. You-Ten, A. Wakeham, H. E. H. Fong, C. C. Cheung, and T. W. Mak (2006)
PNAS 103, 1834-1839
 |  Abstract »  |  Full Text »  |  PDF »

Expression of Neutrophil Gelatinase-Associated Lipocalin in Atherosclerosis and Myocardial Infarction.

A.-L. Hemdahl, A. Gabrielsen, C. Zhu, P. Eriksson, U. Hedin, J. Kastrup, P. Thoren, and G. K. Hansson (2006)
Arterioscler Thromb Vasc Biol 26, 136-142
 |  Abstract »  |  Full Text »  |  PDF »

Gene Expression Profiling of 17{beta}-Estradiol and Genistein Effects on Mouse Thymus.

V. Selvaraj, D. Bunick, C. Finnigan-Bunick, R. W. Johnson, H. Wang, L. Liu, and P. S. Cooke (2005)
Toxicol. Sci. 87, 97-112
 |  Abstract »  |  Full Text »  |  PDF »

Advanced glycation endproduct-induced aging of the retinal pigment epithelium and choroid: A comprehensive transcriptional response.

J. Tian, K. Ishibashi, K. Ishibashi, K. Reiser, R. Grebe, S. Biswal, P. Gehlbach, and J. T. Handa (2005)
PNAS 102, 11846-11851
 |  Abstract »  |  Full Text »  |  PDF »

Lipocalin 2 Diminishes Invasiveness and Metastasis of Ras-transformed Cells.

J.-i. Hanai, T. Mammoto, P. Seth, K. Mori, S. A. Karumanchi, J. Barasch, and V. P. Sukhatme (2005)
J. Biol. Chem. 280, 13641-13647
 |  Abstract »  |  Full Text »  |  PDF »

Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-{alpha}-induced genes in bone cells.

F. Shen, M. J. Ruddy, P. Plamondon, and S. L. Gaffen (2005)
J. Leukoc. Biol. 77, 388-399
 |  Abstract »  |  Full Text »  |  PDF »

Transcriptional Profiles of Intestinal Tumors in ApcMin Mice are Unique from those of Embryonic Intestine and Identify Novel Gene Targets Dysregulated in Human Colorectal Tumors.

T. Reichling, K. H. Goss, D. J. Carson, R. W. Holdcraft, C. Ley-Ebert, D. Witte, B. J. Aronow, and J. Groden (2005)
Cancer Res. 65, 166-176
 |  Abstract »  |  Full Text »  |  PDF »

Amelioration of Ischemic Acute Renal Injury by Neutrophil Gelatinase-Associated Lipocalin.

J. Mishra, K. Mori, Q. Ma, C. Kelly, J. Yang, M. Mitsnefes, J. Barasch, and P. Devarajan (2004)
J. Am. Soc. Nephrol. 15, 3073-3082
 |  Abstract »  |  Full Text »  |  PDF »

The PP2A-Associated Protein {alpha}4 Is an Essential Inhibitor of Apoptosis.

M. Kong, C. J. Fox, J. Mu, L. Solt, A. Xu, R. M. Cinalli, M. J. Birnbaum, T. Lindsten, and C. B. Thompson (2004)
Science 306, 695-698
 |  Abstract »  |  Full Text »  |  PDF »

Hepatic Temporal Gene Expression Profiling in Helicobacter hepaticus-Infected A/JCr Mice.

S. R. Boutin, A. B. Rogers, Zeli Shen, R. C. Fry, J. A. Love, P. R. Nambiar, S. Suerbaum, and J. G. Fox (2004)
Toxicol Pathol 32, 678-693
 |  Abstract »  |  PDF »

Antiapoptotic Protein Partners Fortilin and MCL1 Independently Protect Cells from 5-Fluorouracil-induced Cytotoxicity.

P. Graidist, A. Phongdara, and K. Fujise (2004)
J. Biol. Chem. 279, 40868-40875
 |  Abstract »  |  Full Text »  |  PDF »

Microarray Analysis Supports a Role for CCAAT/Enhancer-binding Protein-{beta} in Brain Injury.

M. Cortes-Canteli, M. Wagner, W. Ansorge, and A. Perez-Castillo (2004)
J. Biol. Chem. 279, 14409-14417
 |  Abstract »  |  Full Text »  |  PDF »

Identification of a Cytokine-induced Antiapoptotic Molecule Anamorsin Essential for Definitive Hematopoiesis.

H. Shibayama, E. Takai, I. Matsumura, M. Kouno, E. Morii, Y. Kitamura, J. Takeda, and Y. Kanakura (2004)
J. Exp. Med. 199, 581-592
 |  Abstract »  |  Full Text »  |  PDF »

Identification of Neutrophil Gelatinase-Associated Lipocalin as a Novel Early Urinary Biomarker for Ischemic Renal Injury.

J. Mishra, Q. Ma, A. Prada, M. Mitsnefes, K. Zahedi, J. Yang, J. Barasch, and P. Devarajan (2003)
J. Am. Soc. Nephrol. 14, 2534-2543
 |  Abstract »  |  Full Text »  |  PDF »

Transcriptional Program of Apoptosis Induction following Interleukin 2 Deprivation: Identification of RC3, a Calcium/Calmodulin Binding Protein, as a Novel Proapoptotic Factor.

L. R. Devireddy and M. R. Green (2003)
Mol. Cell. Biol. 23, 4532-4541
 |  Abstract »  |  Full Text »  |  PDF »

Iron, lipocalin, and kidney epithelia.

J. Yang, K. Mori, J. Y. Li, and J. Barasch (2003)
Am J Physiol Renal Physiol 285, F9-F18
 |  Abstract »  |  Full Text »  |  PDF »

Signaling Differences from the A and B Isoforms of the Insulin Receptor (IR) in 32D Cells in the Presence or Absence of IR Substrate-1.

L. Sciacca, M. Prisco, A. Wu, A. Belfiore, R. Vigneri, and R. Baserga (2003)
Endocrinology 144, 2650-2658
 |  Abstract »  |  Full Text »  |  PDF »

Antisense Down-regulation of Lipocalin-interacting Membrane Receptor Expression Inhibits Cellular Internalization of Lipocalin-1 in Human NT2 Cells.

P. Wojnar, M. Lechner, and B. Redl (2003)
J. Biol. Chem. 278, 16209-16215
 |  Abstract »  |  Full Text »  |  PDF »

Enterobactin: An archetype for microbial iron transport.

K. N. Raymond, E. A. Dertz, and S. S. Kim (2003)
PNAS 100, 3584-3588
 |  Abstract »  |  Full Text »  |  PDF »

Anti-apoptotic Signaling by the Interleukin-2 Receptor Reveals a Function for Cytoplasmic Tyrosine Residues within the Common gamma (gamma c) Receptor Subunit.

M. J. Lindemann, M. Benczik, and S. L. Gaffen (2003)
J. Biol. Chem. 278, 10239-10249
 |  Abstract »  |  Full Text »  |  PDF »

Small Unstable Apoptotic Protein, an Apoptosis-associated Protein, Suppresses Proliferation of Myeloid Cells.

S. J. Baker (2003)
Cancer Res. 63, 705-712
 |  Abstract »  |  Full Text »  |  PDF »

Broad-spectrum caspase inhibition paradoxically augments cell death in TNF-alpha -stimulated neutrophils.

C.-Y. Liu, A. Takemasa, W. C. Liles, R. B. Goodman, M. Jonas, H. Rosen, E. Chi, R. K. Winn, J. M. Harlan, and P. I. Chuang (2003)
Blood 101, 295-304
 |  Abstract »  |  Full Text »  |  PDF »

Nuclear Translocation of Insulin Receptor Substrate-1 by the Simian Virus 40 T Antigen and the Activated Type 1 Insulin-like Growth Factor Receptor.

M. Prisco, F. Santini, R. Baffa, M. Liu, R. Drakas, A. Wu, and R. Baserga (2002)
J. Biol. Chem. 277, 32078-32085
 |  Abstract »  |  Full Text »  |  PDF »

Cellular and Molecular Targets of Estrogen in Normal Human Breast Tissue.

P. Seth, D. Porter, J. Lahti-Domenici, Y. Geng, A. Richardson, and K. Polyak (2002)
Cancer Res. 62, 4540-4544
 |  Abstract »  |  Full Text »  |  PDF »

The Avian Chb6 Alloantigen Triggers Apoptosis in a Mammalian Cell Line.

J. Pifer, D. Robison, and P. E. Funk (2002)
J. Immunol. 169, 1372-1378
 |  Abstract »  |  Full Text »  |  PDF »

Inhibition of apoptosis by ATFx: a novel role for a member of the ATF/CREB family of mammalian bZIP transcription factors.

S. P. Persengiev, L. R. Devireddy, and M. R. Green (2002)
Genes & Dev. 16, 1806-1814
 |  Abstract »  |  Full Text »  |  PDF »

Perineuronal Oligodendrocytes Protect against Neuronal Apoptosis through the Production of Lipocalin-Type Prostaglandin D Synthase in a Genetic Demyelinating Model.

M. Taniike, I. Mohri, N. Eguchi, C. T. Beuckmann, K. Suzuki, and Y. Urade (2002)
J. Neurosci. 22, 4885-4896
 |  Abstract »  |  Full Text »  |  PDF »

Programmed cell death takes flight: genetic and genomic approaches to gene discovery in Drosophila.

S. Gorski and M. Marra (2002)
Physiol Genomics 9, 59-69
 |  Abstract »  |  Full Text »  |  PDF »

Expression Profiling of Palmitate- and Oleate-Regulated Genes Provides Novel Insights Into the Effects of Chronic Lipid Exposure on Pancreatic {beta}-Cell Function.

A. K. Busch, D. Cordery, G. S. Denyer, and T. J. Biden (2002)
Diabetes 51, 977-987
 |  Abstract »  |  Full Text »  |  PDF »

Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells.

F. Zhan, J. Hardin, B. Kordsmeier, K. Bumm, M. Zheng, E. Tian, R. Sanderson, Y. Yang, C. Wilson, M. Zangari, et al. (2002)
Blood 99, 1745-1757
 |  Abstract »  |  Full Text »  |  PDF »