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Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis

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Abstract

Progranulin (Pgrn) is a pluripotent secreted growth factor that mediates cell cycle progression and cell motility. It activates the extracellular regulated kinases and phosphatidyl inositol-3 kinase signal cascades, among others, and increases expression of cyclins D and B. Structurally, it belongs to none of the well-established growth factor families. It regulates developmental events as diverse as the onset of cavitation in the preimplantation embryo and male-specific brain differentiation. During wound repair it promotes granulation and neovascularization. It regulates inflammation through a tripartite loop with secretory leukocyte protease inhibitor (SLPI) which protects pgrn from proteolysis, and elastase, which digests it to smaller peptides. Intact pgrn is anti-inflammatory through the inhibition of some of the actions of tumor necrosis factor, while the proteolytic peptides may stimulate the production of proinflammatory cytokines such as interleukin 8. Pgrn is highly expressed in aggressive cancer cell lines and clinical specimens including breast, ovarian, and renal cancers as well as gliomas. In experimental systems it confers an aggressive phenotype on poorly tumorigenic epithelial cancer cells. The malignancy of highly tumorigenic progranulin-expressing cell lines depends on the expression level of the pgrn gene since attenuating pgrn mRNA levels in pgrn-responsive cells greatly inhibits tumor progression. Given its actions in wound repair and tumorigenesis pgrn may prove a useful clinical target, both for prognosis and for therapy.

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Abbreviations

EGF :

Epidermal growth factor

FAK :

Focal adhesion kinase

FGF :

Fibroblast growth factor

grn/epi :

Granulin-epithelin

IGF :

Insulin-like growth factor

MAPK :

Mitogen-activated protein kinase

MEF :

Mouse embryo fibroblast

PDGF :

Platelet-derived growth factor

Pgrn :

Progranulin

PI-3K :

Phosphatidylinositol-3 kinase

SLPI :

Secretory leukocyte protease inhibitor

TGF-β :

Transforming growth factor-β

TGFe :

Epithelial transforming growth factor

TNF :

Tumor necrosis factor

VEGF :

Vascular endothelial growth factor

References

  1. Bateman A, Bennett HP (1998) Granulins: the structure and function of an emerging family of growth factors. J Endocrinol 158:145–151

    CAS  PubMed  Google Scholar 

  2. Zanocco-Marani T, Bateman A, Romano G, Valentinis B, He ZH, Baserga R (1999) Biological activities and signaling pathways of the granulin/epithelin precursor. Cancer Res 59:5331–5340

    CAS  PubMed  Google Scholar 

  3. Plowman GD, Green JM, Neubauer MG, Buckley SD, McDonald VL, Todaro GJ, Shoyab M (1992) The epithelin precursor encodes two proteins with opposing activities on epithelial cell growth. J Biol Chem 267:13073–13078

    CAS  PubMed  Google Scholar 

  4. Zhou J, Gao G, Crabb JW, Serrero G (1993) Purification of an autocrine growth factor homologous with mouse epithelin precursor from a highly tumorigenic cell line. J Biol Chem 268:10863–10869

    CAS  PubMed  Google Scholar 

  5. Baba T, Hoff HB, 3rd, Nemoto H, Lee H, Orth J, Arai Y, Gerton GL (1993) Acrogranin, an acrosomal cysteine-rich glycoprotein, is the precursor of the growth-modulating peptides, granulins, and epithelins, and is expressed in somatic as well as male germ cells. Mol Reprod Dev 34:233–243

    CAS  PubMed  Google Scholar 

  6. Bhandari V, Palfree RG, Bateman A (1992) Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains. Proc Natl Acad Sci U S A 89:1715–1719

    CAS  PubMed  Google Scholar 

  7. Hrabal R, Chen Z, James S, Bennett HP, Ni F (1996) The hairpin stack fold, a novel protein architecture for a new family of protein growth factors. Nat Struct Biol 3:747–752

    CAS  PubMed  Google Scholar 

  8. Tolkatchev D, Ng A, Vranken W, Ni F (2000) Design and solution structure of a well-folded stack of two beta-hairpins based on the amino-terminal fragment of human granulin A. Biochemistry 39:2878–2886

    Article  CAS  PubMed  Google Scholar 

  9. Avrova AO, Stewart HE, De Jong WD, Heilbronn J, Lyon GD, Birch PR (1999) A cysteine protease gene is expressed early in resistant potato interactions with Phytophthora infestans. Mol Plant Microbe Interact 12:1114–1119

    CAS  PubMed  Google Scholar 

  10. Bateman A, Belcourt D, Bennett H, Lazure C, Solomon S (1990) Granulins, a novel class of peptide from leukocytes. Biochem Biophys Res Commun 173:1161–1168

    CAS  PubMed  Google Scholar 

  11. Sparro G, Galdenzi G, Eleuteri AM, Angeletti M, Schroeder W, Fioretti E (1997) Isolation and N-terminal sequence of multiple forms of granulins in human urine. Protein Expr Purif 10:169–174

    Article  CAS  PubMed  Google Scholar 

  12. Shoyab M, McDonald VL, Byles C, Todaro GJ, Plowman GD (1990) Epithelins 1 and 2: isolation and characterization of two cysteine-rich growth-modulating proteins. Proc Natl Acad Sci U S A 87:7912–7916

    CAS  PubMed  Google Scholar 

  13. Couto MA, Harwig SS, Cullor JS, Hughes JP, Lehrer RI (1992) Identification of eNAP-1, an antimicrobial peptide from equine neutrophils. Infect Immun 60:3065–3071

    CAS  PubMed  Google Scholar 

  14. Belcourt DR, Lazure C, Bennett HP (1993) Isolation and primary structure of the three major forms of granulin-like peptides from hematopoietic tissues of a teleost fish (Cyprinus carpio). J Biol Chem 268:9230–9237

    CAS  PubMed  Google Scholar 

  15. Belcourt DR, Okawara Y, Fryer JN, Bennett HP (1995) Immunocytochemical localization of granulin-1 to mononuclear phagocytic cells of the teleost fish Cyprinus carpio and Carassius auratus. J Leukoc Biol 57:94–100

    CAS  PubMed  Google Scholar 

  16. Uesaka T, Yano K, Yamasaki M, Ando M (1995) Somatostatin-, vasoactive intestinal peptide-, and granulin-like peptides isolated from intestinal extracts of goldfish, Carassius auratus. Gen Comp Endocrinol 99:298–306

    Article  CAS  PubMed  Google Scholar 

  17. Nakakura N, Hietter H, Van Dorsselaer A, Luu B (1992) Isolation and structural determination of three peptides from the insect Locusta migratoria. Identification of a deoxyhexose-linked peptide. Eur J Biochem 204:147–153

    CAS  PubMed  Google Scholar 

  18. Deloffre L, Sautiere P, Cocquerelle C, Andries JC (1999) Identification of granulin-related peptides in a marine invertebrate, Hediste diversicolor. Bull Soc Zool France 124:337–346

    Google Scholar 

  19. Hong SJ, and Kang KW (1999) Purification of granulin-like polypeptide from the blood-sucking leech, Hirudo nipponia. Protein Expr Purif 16:340–346

    Article  CAS  PubMed  Google Scholar 

  20. Zhu J, Nathan C, Jin W, Sim D, Ashcroft GS, Wahl SM, Lacomis L, Erdjument-Bromage H, Tempst P, Wright CD, Ding A (2002) Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair. Cell 111:867–878

    CAS  PubMed  Google Scholar 

  21. Parnell PG, Wunderlich J, Carter B, Halper J (1992) Transforming growth factor e: amino acid analysis and partial amino acid sequence. Growth Factors 7:65–72

    CAS  PubMed  Google Scholar 

  22. Bhandari V, Bateman A (1992) Structure and chromosomal location of the human granulin gene. Biochem Biophys Res Commun 188:57–63

    CAS  PubMed  Google Scholar 

  23. Bucan M, Gatalica B, Baba T, Gerton GL (1996) Mapping of Grn, the gene encoding the granulin/epithelin precursor (acrogranin), to mouse chromosome 11. Mamm Genome 7:704–705

    Article  CAS  PubMed  Google Scholar 

  24. Bhandari V, Giaid A, Bateman A (1993) The complementary deoxyribonucleic acid sequence, tissue distribution, and cellular localization of the rat granulin precursor. Endocrinology 133:2682–2689

    CAS  PubMed  Google Scholar 

  25. Daniel R, He Z, Carmichael KP, Halper J, Bateman A (2000) Cellular localization of gene expression for progranulin. J Histochem Cytochem 48:999–1009

    CAS  PubMed  Google Scholar 

  26. He Z, Bateman A (1999) Progranulin gene expression regulates epithelial cell growth and promotes tumor growth in vivo. Cancer Res 59:3222–3229

    CAS  PubMed  Google Scholar 

  27. He Z, Ong CH, Halper J, Bateman A (2003) Progranulin is a mediator of the wound response. Nat Med 9:225–229

    Article  CAS  PubMed  Google Scholar 

  28. Xu SQ, Sell C, DuBois GC, Baserga R (1997) A novel growth stimulating activity from BRL-3A cell conditioned medium. Cell Prolif 30:295–307

    CAS  PubMed  Google Scholar 

  29. Xu SQ, Tang D, Chamberlain S, Pronk G, Masiarz FR, Kaur S, Prisco M, Zanocco-Marani T, Baserga R (1998) The granulin/epithelin precursor abrogates the requirement for the insulin-like growth factor 1 receptor for growth in vitro. J Biol Chem 273:20078–20083

    Article  CAS  PubMed  Google Scholar 

  30. Zhang H, Serrero G (1998) Inhibition of tumorigenicity of the teratoma PC cell line by transfection with antisense cDNA for PC cell-derived growth factor (PCDGF, epithelin/granulin precursor). Proc Natl Acad Sci U S A 95:14202–14207

    Article  CAS  PubMed  Google Scholar 

  31. Sell C, Dumenil G, Deveaud C, Miura M, Coppola D, DeAngelis T, Rubin R, Efstratiadis A, Baserga R (1994) Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts. Mol Cell Biol 14:3604–3612

    CAS  PubMed  Google Scholar 

  32. Anakwe OO, Gerton GL (1990) Acrosome biogenesis begins during meiosis: evidence from the synthesis and distribution of an acrosomal glycoprotein, acrogranin, during guinea pig spermatogenesis. Biol Reprod 42:317–328

    CAS  PubMed  Google Scholar 

  33. Diaz-Cueto L, Stein P, Jacobs A, Schultz RM, Gerton GL (2000) Modulation of mouse preimplantation embryo development by acrogranin (epithelin/granulin precursor). Dev Biol 217:406–418

    CAS  PubMed  Google Scholar 

  34. Suzuki M, Matsumuro M, Hirabayashi K, Ogawara M, Nishiahara M, Takahashi M (2000) Oocyte-specific expression of granulin precursor (acrogranin) in rat ovary. J Reprod Dev 46:271

    Article  CAS  Google Scholar 

  35. Daniel R, Daniels E, He Z, Bateman A (2003) Progranulin (Acrogranin/PC cell-derived growth factor/epithelin precursor) is expressed in the placenta, epidermis, microvasculature and brain during murine development. Dev Dyn 227:593–599

    Google Scholar 

  36. Suzuki M, Nishiahara M (2002) Granulin precursor gene: a sex steroid-inducible gene involved in sexual differentiation of the rat brain. Mol Genet Metab 75:31–37

    Article  CAS  PubMed  Google Scholar 

  37. Arnold AP, Gorski RA (1984) Gonadal steroid induction of structural sex differences in the central nervous system. Annu Rev Neurosci 7:413–442

    Article  CAS  PubMed  Google Scholar 

  38. Suzuki M, Yoshida S, Nishihara M, Takahashi M (1998) Identification of a sex steroid-inducible gene in the neonatal rat hypothalamus. Neurosci Lett 242:127–130

    Article  CAS  PubMed  Google Scholar 

  39. Suzuki M, Yonezawa T, Fujioka H, Matuamuro M, Nishihara M (2001) Induction of granulin precursor gene expression by estrogen treatment in neonatal rat hypothalamus. Neurosci Lett 297:199–202

    Article  CAS  PubMed  Google Scholar 

  40. Frankfurt M (1994) Gonadal steroids and neuronal plasticity. Studies in the adult rat hypothalamus. Ann N Y Acad Sci 743:45–59

    CAS  PubMed  Google Scholar 

  41. Suzuki M, Bannai M, Matsumuro M, Furuhata Y, Ikemura R, Kuranaga E, Kaneda Y, Nishihara M, Takahashi M (2000) Suppression of copulatory behavior by intracerebroventricular infusion of antisense oligodeoxynucleotide of granulin in neonatal male rats. Physiol Behav 68:707–713

    Article  CAS  PubMed  Google Scholar 

  42. Wertz K, Herrmann BG (2000) Large-scale screen for genes involved in gonad development. Mech Dev 98:51–70

    Article  CAS  PubMed  Google Scholar 

  43. Martin P (1997) Wound healing-aiming for perfect skin regeneration. Science 276:75–81

    Google Scholar 

  44. Singer AJ, Clark RA (1999) Cutaneous wound healing. N Engl J Med 341:738–746

    CAS  PubMed  Google Scholar 

  45. Kasama T, Kobayashi K, Yajima N, Shiozawa F, Yoda Y, Takeuchi HT, Mori Y, Negishi M, Ide H, Adachi M (2000) Expression of vascular endothelial growth factor by synovial fluid neutrophils in rheumatoid arthritis (RA). Clin Exp Immunol 121:533–538

    Article  CAS  PubMed  Google Scholar 

  46. McCourt M, Wang JH, Sookhai S, Redmond HP (2001) Activated human neutrophils release hepatocyte growth factor/scatter factor. Eur J Surg Oncol 27:396–403

    Article  CAS  PubMed  Google Scholar 

  47. Grotendorst GR, Smale G, Pencev D (1989) Production of transforming growth factor beta by human peripheral blood monocytes and neutrophils. J Cell Physiol 140:396–402

    CAS  PubMed  Google Scholar 

  48. Sunderkotter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C (1994) Macrophages and angiogenesis. J Leukoc Biol 55:410–422

    CAS  PubMed  Google Scholar 

  49. Werner S, Peters KG, Longaker MT, Fuller-Pace F, Banda MJ, Williams LT (1992) Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc Natl Acad Sci U S A 89:6896–6900

    CAS  PubMed  Google Scholar 

  50. Ihn H (2002) Pathogenesis of fibrosis: role of TGF-beta and CTGF. Curr Opin Rheumatol 14:681–685

    Article  CAS  PubMed  Google Scholar 

  51. Nicosia RF, Ottinetti A (1990) Modulation of microvascular growth and morphogenesis by reconstituted basement membrane gel in three-dimensional cultures of rat aorta: a comparative study of angiogenesis in matrigel, collagen, fibrin, and plasma clot. In Vitro Cell Dev Biol 26:119–128

    CAS  PubMed  Google Scholar 

  52. Bussolati B, Dunk C, Grohman M, Kontos CD, Mason J, Ahmed A (2001) Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide. Am J Pathol 159:993–1008

    CAS  PubMed  Google Scholar 

  53. Kitajima I, Unoki K, Maruyama I (1999) Phosphorothioate oligodeoxynucleotides inhibit basic fibroblast growth factor-induced angiogenesis in vitro and in vivo. Antisense Nucleic Acid Drug Dev 9:233–239

    CAS  PubMed  Google Scholar 

  54. Jones MB, Michener CM, Blanchette JO, Kuznetsov VA, Raffeld M, Serrero G, Emmert-Buck MR, Petricoin EF, Krizman DB, Liotta LA, Kohn EC (2003) The granulin-epithelin precursor/PC-cell-derived growth factor is a growth factor for epithelial ovarian cancer. Clin Cancer Res 9:44–51

    CAS  PubMed  Google Scholar 

  55. Garcia-Cardena G, Comander J, Anderson KR, Blackman BR, Gimbrone MA Jr (2001) Biomechanical activation of vascular endothelium as a determinant of its functional phenotype. Proc Natl Acad Sci U S A 98:4478–4485

    Article  CAS  PubMed  Google Scholar 

  56. Passerini AG, Milsted A, Rittgers SE (2003) Shear stress magnitude and directionality modulate growth factor gene expression in preconditioned vascular endothelial cells. J Vasc Surg 37:182–190

    Article  PubMed  Google Scholar 

  57. Jin FY, Nathan C, Radzioch D, Ding A (1997) Secretory leukocyte protease inhibitor: a macrophage product induced by and antagonistic to bacterial lipopolysaccharide. Cell 88:417–426

    CAS  PubMed  Google Scholar 

  58. Bhandari V, Daniel R, Lim PS, Bateman A (1996) Structural and functional analysis of a promoter of the human granulin/epithelin gene. Biochem J 319:441–447

    CAS  PubMed  Google Scholar 

  59. Baba T, Nemoto H, Watanabe K, Arai Y, Gerton GL (1993) Exon/intron organization of the gene encoding the mouse epithelin/granulin precursor (acrogranin). FEBS Lett 322:89–94

    Article  CAS  PubMed  Google Scholar 

  60. Subrahmanyam YV, Yamaga S, Prashar Y, Lee HH, Hoe NP, Kluger Y, Gerstein M, Goguen JD, Newburger PE, Weissman SM (2001) RNA expression patterns change dramatically in human neutrophils exposed to bacteria. Blood 97:2457–2468

    Article  CAS  PubMed  Google Scholar 

  61. Justen HP, Grunewald E, Totzke G, Gouni-Berthold I, Sachinidis A, Wessinghage D, Vetter H, Schulze-Osthoff K, Ko Y (2000) Differential gene expression in synovium of rheumatoid arthritis and osteoarthritis. Mol Cell Biol Res Commun 3:165–172

    Article  CAS  PubMed  Google Scholar 

  62. Choy EH, Panayi GS (2001) Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 344:907–916

    CAS  PubMed  Google Scholar 

  63. Matzilevich DA, Rall JM, Moore AN, Grill RJ, Dash PK (2002) High-density microarray analysis of hippocampal gene expression following experimental brain injury. J Neurosci Res 67:646–663

    Article  CAS  PubMed  Google Scholar 

  64. Johnston C, Jiang W, Chu T, Levine B (2001) Identification of genes involved in the host response to neurovirulent alphavirus infection. J Virol 75:10431–10445

    Article  CAS  PubMed  Google Scholar 

  65. Baker CA, Manuelidis L (2003) Unique inflammatory RNA profiles of microglia in Creutzfeldt-Jakob disease. Proc Natl Acad Sci U S A 100:675–679

    Article  CAS  PubMed  Google Scholar 

  66. Ohmi K, Greenberg DS, Rajavel KS, Ryazantsev S, Li HH, Neufeld EF (2003) Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB. Proc Natl Acad Sci U S A 100:1902–1907

    Article  CAS  PubMed  Google Scholar 

  67. Malaspina A, Kaushik N, de Belleroche J (2001) Differential expression of 14 genes in amyotrophic lateral sclerosis spinal cord detected using gridded cDNA arrays. J Neurochem 77:132–145

    CAS  PubMed  Google Scholar 

  68. Hall ED, Oostveen JA, Gurney ME (1998) Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23:249–256

    Article  CAS  PubMed  Google Scholar 

  69. Cross M, Dexter TM (1991) Growth factors in development, transformation, and tumorigenesis. Cell 64:271–280

    CAS  PubMed  Google Scholar 

  70. Aaronson SA (1991) Growth factors and cancer. Science 254:1146–1153

    CAS  PubMed  Google Scholar 

  71. Lu R, Serrero G (2000) Inhibition of PC cell-derived growth factor (PCDGF, epithelin/granulin precursor) expression by antisense PCDGF cDNA transfection inhibits tumorigenicity of the human breast carcinoma cell line MDA-MB-468. Proc Natl Acad Sci U S A 97:3993–3998

    Article  CAS  PubMed  Google Scholar 

  72. Lu R, Serrero G (2001) Mediation of estrogen mitogenic effect in human breast cancer MCF-7 cells by PC-cell-derived growth factor (PCDGF/granulin precursor). Proc Natl Acad Sci U S A 98:142–147

    Article  CAS  PubMed  Google Scholar 

  73. Leerkes MR, Caballero OL, Mackay A, Torloni H, O'Hare MJ, Simpson AJ, de Souza SJ (2002) In silico comparison of the transcriptome derived from purified normal breast cells and breast tumor cell lines reveals candidate upregulated genes in breast tumor cells. Genomics 79:257–265

    Article  CAS  PubMed  Google Scholar 

  74. Egland KA, Vincent JJ, Strausberg R, Lee B, Pastan I (2003) Discovery of the breast cancer gene BASE using a molecular approach to enrich for genes encoding membrane and secreted proteins. Proc Natl Acad Sci U S A 100:1099–1104

    Article  CAS  PubMed  Google Scholar 

  75. Donald CD, Laddu A, Chandham P, Lim SD, Cohen C, Amin M, Gerton GL, Marshall FF, Petros JA (2001) Expression of progranulin and the epithelin/granulin precursor acrogranin correlates with neoplastic state in renal epithelium. Anticancer Res 21:3739–3742

    CAS  PubMed  Google Scholar 

  76. Ali SM, Nambi P, Fredrickson TA, Brooks DP (1999) Epithelin mRNA expression in polycystic kidney disease. Peptides 20:1489–1495

    Article  CAS  PubMed  Google Scholar 

  77. Line A, Stengrevics A, Slucka Z, Li G, Jankevics E, Rees RC (2002) Serological identification and expression analysis of gastric cancer-associated genes. Br J Cancer 86:1824–1830

    CAS  PubMed  Google Scholar 

  78. Liau LM, Lallone RL, Seitz RS, Buznikov A, Gregg JP, Kornblum HI, Nelson SF, Bronstein JM (2000) Identification of a human glioma-associated growth factor gene, granulin, using differential immuno-absorption. Cancer Res 60:1353–1360

    CAS  PubMed  Google Scholar 

  79. Markert JM, Fuller CM, Gillespie GY, Bubien JK, McLean LA, Hong RL, Lee K, Gullans SR, Mapstone TB, Benos DJ (2001) Differential gene expression profiling in human brain tumors. Physiol Genomics 5:21–33

    Google Scholar 

  80. Virtaneva K, Wright FA, Tanner SM, Yuan B, Lemon WJ, Caligiuri MA, Bloomfield CD, de La Chapelle A, Krahe R (2001) Expression profiling reveals fundamental biological differences in acute myeloid leukemia with isolated trisomy 8 and normal cytogenetics. Proc Natl Acad Sci U S A 98:1124–1129

    Article  CAS  PubMed  Google Scholar 

  81. Chow ML, Moler EJ, Mian IS (2001) Identifying marker genes in transcription profiling data using a mixture of feature relevance experts. Physiol Genomics 5:99–111

    CAS  PubMed  Google Scholar 

  82. Wang W, Hayashi J, Kim WE, Serrero G (2003) PC cell-derived growth factor (granulin precursor) expression and action in human multiple myeloma. Clin Cancer Res 9:2221–2228

    CAS  PubMed  Google Scholar 

  83. Halper J, Moses HL (1983) Epithelial tissue-derived growth factor-like polypeptides. Cancer Res 43:1972–1979

    CAS  PubMed  Google Scholar 

  84. Halper J, Moses HL (1987) Purification and characterization of a novel transforming growth factor. Cancer Res 47:4552–4559

    CAS  PubMed  Google Scholar 

  85. He Z, Ismail A, Kriazhev L, Sadvakassova G, Bateman A (2002) Progranulin (PC-cell-derived growth factor/acrogranin) regulates invasion and cell survival. Cancer Res 62:5590–5596

    CAS  PubMed  Google Scholar 

  86. Grossmann J (2002) Molecular mechanisms of "detachment-induced apoptosis-Anoikis." Apoptosis 7:247–260

    Google Scholar 

  87. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    CAS  PubMed  Google Scholar 

  88. Kudoh K, Ramanna M, Ravatn R, Elkahloun AG, Bittner ML, Meltzer PS, Trent JM, Dalton WS, Chin KV (2000) Monitoring the expression profiles of doxorubicin-induced and doxorubicin-resistant cancer cells by cDNA microarray. Cancer Res 60:4161–4166

    CAS  PubMed  Google Scholar 

  89. Xia X, Serrero G (1998) Identification of cell surface binding sites for PC-cell-derived growth factor, PCDGF (epithelin/granulin precursor) on epithelial cells and fibroblasts. Biochem Biophys Res Commun 245:539–543

    Article  CAS  PubMed  Google Scholar 

  90. Culouscou JM, Carlton GW, Shoyab M (1993) Biochemical analysis of the epithelin receptor. J Biol Chem 268:10458–10462

    CAS  PubMed  Google Scholar 

  91. Parnell PG, Carter BJ, Halper J (1995) Identification of a membrane-associated receptor for transforming growth factor type E. J Recept Signal Transduct Res 15:747–756

    CAS  PubMed  Google Scholar 

  92. Baladron V, Ruiz-Hidalgo MJ, Bonvini E, Gubina E, Notario V, Laborda J (2002) The EGF-like homeotic protein dlk affects cell growth and interacts with growth-modulating molecules in the yeast two-hybrid system. Biochem Biophys Res Commun 291:193–204

    Article  CAS  PubMed  Google Scholar 

  93. Laborda J (2000) The role of the epidermal growth factor-like protein dlk in cell differentiation. Histol Histopathol 15:119–129

    CAS  PubMed  Google Scholar 

  94. Stiles CD, Capone GT, Scher CD, Antoniades HN, Van Wyk JJ, Pledger WJ (1979) Dual control of cell growth by somatomedins and platelet-derived growth factor. Proc Natl Acad Sci U S A 76:1279–1283

    CAS  PubMed  Google Scholar 

  95. Scher CD, Shepard RC, Antoniades HN, Stiles CD (1979) Platelet-derived growth factor and the regulation of the mammalian fibroblast cell cycle. Biochim Biophys Acta 560:217–241

    Article  CAS  PubMed  Google Scholar 

  96. Cristofalo VJ, Phillips PD, Sorger T, Gerhard G (1989) Alterations in the responsiveness of senescent cells to growth factors. J Gerontol 44:55–62

    CAS  PubMed  Google Scholar 

  97. King RW, Jackson PK, Kirschner MW (1994) Mitosis in transition. Cell 79:563–571

    CAS  PubMed  Google Scholar 

  98. Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80:179–185

    CAS  PubMed  Google Scholar 

  99. Weber JD, Raben DM, Phillips PJ, Baldassare JJ (1997) Sustained activation of extracellular-signal-regulated kinase 1 (ERK1) is required for the continued expression of cyclin D1 in G1 phase. Biochem J 326:61–68

    CAS  PubMed  Google Scholar 

  100. Khokhlatchev AV, Canagarajah B, Wilsbacher J, Robinson M, Atkinson M, Goldsmith E, Cobb MH (1998) Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation. Cell 93:605–615

    CAS  PubMed  Google Scholar 

  101. Balmanno K, Cook SJ (1999) Sustained MAP kinase activation is required for the expression of cyclin D1, p21Cip1 and a subset of AP-1 proteins in CCL39 cells. Oncogene 18:3085–3097

    CAS  PubMed  Google Scholar 

  102. Cary LA, Guan JL (1999) Focal adhesion kinase in integrin-mediated signaling. Front Biosci 4:D102–D113

    CAS  PubMed  Google Scholar 

  103. Hauck CR, Hsia DA, Schlaepfer DD (2002) The focal adhesion kinase-a regulator of cell migration and invasion. IUBMB Life 53:115–119

    CAS  PubMed  Google Scholar 

  104. Abbi S, Guan JL (2002) Focal adhesion kinase: protein interactions and cellular functions. Histol Histopathol 17:1163–1171

    CAS  PubMed  Google Scholar 

  105. Trinh DP, Brown KM, Jeang KT (1999) Epithelin/granulin growth factors: extracellular cofactors for HIV-1 and HIV-2 Tat proteins. Biochem Biophys Res Commun 256:299–306

    Article  CAS  PubMed  Google Scholar 

  106. Hoque M, Young TM, Lee CG, Serrero G, Mathews MB, Pe'ery T (2003) The growth factor granulin interacts with cyclin T1 and modulates P-TEFb-dependent transcription. Mol Cell Biol 23:1688–1702

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

A.B. acknowledges the Canadian Institutes for Health Research and the National Cancer Institute of Canada for financial support.

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  1. Vascular Cell Biology and Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA, 02215, USA

    Zhiheng He

  2. Division of Experimental Medicine, McGill University, and Endocrine Research Laboratory, Royal Victoria Hospital, 687 Pine Ave West, Montreal, Quebec, H3A 1A1, Canada

    Andrew Bateman

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He, Z., Bateman, A. Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med 81, 600–612 (2003). https://doi.org/10.1007/s00109-003-0474-3

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