Critical Prosurvival Roles for C/EBPβ and Insulin-Like Growth Factor I in Macrophage Tumor Cells

Jennifer Wessells, Shoshana Yakar, Peter F. Johnson

Research output: Contribution to journalArticle

Abstract

One of the hallmarks of leukemic cells is their ability to proliferate and survive in the absence of exogenous growth factors (GFs). However, the molecular mechanisms used by myeloid tumor cells to escape apoptosis are not fully understood. Here we report that Myc/Raf-transformed macrophages require the transcription factor C/EBPβ to prevent cell death. In contrast to wild-type cells, C/EBPβ-/- macrophages were completely dependent on macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor for survival and displayed impaired tumorigenicity in vivo. Microarray analysis revealed that C/EBPβ-deficient cells expressed significantly reduced levels of the prosurvival factor insulin-like growth factor I (IGF-I). Overexpression of C/EBPβ stimulated transcription from the IGF-I promoter, indicating that IGF-I is a direct transcriptional target of C/EBPβ. Serological neutralization of IGF-I in C/EBPβ+/+ tumor cell cultures induced apoptosis, showing that IGF-I functions as an autocrine survival factor in these cells. Macrophage tumor cells derived from IGF-I-/- mice were GF dependent, similar to C/EBPβ-deficient cells. Forced expression of either C/EBPβ or IGF-I in C/EBPβ -/- bone marrow cells restored Myc/Raf-induced transformation and permitted neoplastic growth without exogenous GFs. Thus, our findings demonstrate that C/EBPβ is essential for oncogenic transformation of macrophages and functions at least in part by regulating expression of the survival factor IGF-I.

Original languageEnglish (US)
Pages (from-to)3238-3250
Number of pages13
JournalMolecular and Cellular Biology
Volume24
Issue number8
DOIs
StatePublished - Apr 2004

Fingerprint

Insulin-Like Growth Factor I
Macrophages
Neoplasms
Intercellular Signaling Peptides and Proteins
Apoptosis
Macrophage Colony-Stimulating Factor
Myeloid Cells
Microarray Analysis
Granulocyte-Macrophage Colony-Stimulating Factor
Bone Marrow Cells
Cell Death
Transcription Factors
Cell Culture Techniques
Growth

ASJC Scopus subject areas

  • Cell Biology
  • Genetics
  • Molecular Biology

Cite this

Critical Prosurvival Roles for C/EBPβ and Insulin-Like Growth Factor I in Macrophage Tumor Cells. / Wessells, Jennifer; Yakar, Shoshana; Johnson, Peter F.

In: Molecular and Cellular Biology, Vol. 24, No. 8, 04.2004, p. 3238-3250.

Research output: Contribution to journalArticle

@article{6146107c5abc4cd4af9b7c91aa8f8904,
title = "Critical Prosurvival Roles for C/EBPβ and Insulin-Like Growth Factor I in Macrophage Tumor Cells",
abstract = "One of the hallmarks of leukemic cells is their ability to proliferate and survive in the absence of exogenous growth factors (GFs). However, the molecular mechanisms used by myeloid tumor cells to escape apoptosis are not fully understood. Here we report that Myc/Raf-transformed macrophages require the transcription factor C/EBPβ to prevent cell death. In contrast to wild-type cells, C/EBPβ-/- macrophages were completely dependent on macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor for survival and displayed impaired tumorigenicity in vivo. Microarray analysis revealed that C/EBPβ-deficient cells expressed significantly reduced levels of the prosurvival factor insulin-like growth factor I (IGF-I). Overexpression of C/EBPβ stimulated transcription from the IGF-I promoter, indicating that IGF-I is a direct transcriptional target of C/EBPβ. Serological neutralization of IGF-I in C/EBPβ+/+ tumor cell cultures induced apoptosis, showing that IGF-I functions as an autocrine survival factor in these cells. Macrophage tumor cells derived from IGF-I-/- mice were GF dependent, similar to C/EBPβ-deficient cells. Forced expression of either C/EBPβ or IGF-I in C/EBPβ -/- bone marrow cells restored Myc/Raf-induced transformation and permitted neoplastic growth without exogenous GFs. Thus, our findings demonstrate that C/EBPβ is essential for oncogenic transformation of macrophages and functions at least in part by regulating expression of the survival factor IGF-I.",
author = "Jennifer Wessells and Shoshana Yakar and Johnson, {Peter F.}",
year = "2004",
month = "4",
doi = "10.1128/MCB.24.8.3238-3250.2004",
language = "English (US)",
volume = "24",
pages = "3238--3250",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "8",

}

TY - JOUR

T1 - Critical Prosurvival Roles for C/EBPβ and Insulin-Like Growth Factor I in Macrophage Tumor Cells

AU - Wessells, Jennifer

AU - Yakar, Shoshana

AU - Johnson, Peter F.

PY - 2004/4

Y1 - 2004/4

N2 - One of the hallmarks of leukemic cells is their ability to proliferate and survive in the absence of exogenous growth factors (GFs). However, the molecular mechanisms used by myeloid tumor cells to escape apoptosis are not fully understood. Here we report that Myc/Raf-transformed macrophages require the transcription factor C/EBPβ to prevent cell death. In contrast to wild-type cells, C/EBPβ-/- macrophages were completely dependent on macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor for survival and displayed impaired tumorigenicity in vivo. Microarray analysis revealed that C/EBPβ-deficient cells expressed significantly reduced levels of the prosurvival factor insulin-like growth factor I (IGF-I). Overexpression of C/EBPβ stimulated transcription from the IGF-I promoter, indicating that IGF-I is a direct transcriptional target of C/EBPβ. Serological neutralization of IGF-I in C/EBPβ+/+ tumor cell cultures induced apoptosis, showing that IGF-I functions as an autocrine survival factor in these cells. Macrophage tumor cells derived from IGF-I-/- mice were GF dependent, similar to C/EBPβ-deficient cells. Forced expression of either C/EBPβ or IGF-I in C/EBPβ -/- bone marrow cells restored Myc/Raf-induced transformation and permitted neoplastic growth without exogenous GFs. Thus, our findings demonstrate that C/EBPβ is essential for oncogenic transformation of macrophages and functions at least in part by regulating expression of the survival factor IGF-I.

AB - One of the hallmarks of leukemic cells is their ability to proliferate and survive in the absence of exogenous growth factors (GFs). However, the molecular mechanisms used by myeloid tumor cells to escape apoptosis are not fully understood. Here we report that Myc/Raf-transformed macrophages require the transcription factor C/EBPβ to prevent cell death. In contrast to wild-type cells, C/EBPβ-/- macrophages were completely dependent on macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor for survival and displayed impaired tumorigenicity in vivo. Microarray analysis revealed that C/EBPβ-deficient cells expressed significantly reduced levels of the prosurvival factor insulin-like growth factor I (IGF-I). Overexpression of C/EBPβ stimulated transcription from the IGF-I promoter, indicating that IGF-I is a direct transcriptional target of C/EBPβ. Serological neutralization of IGF-I in C/EBPβ+/+ tumor cell cultures induced apoptosis, showing that IGF-I functions as an autocrine survival factor in these cells. Macrophage tumor cells derived from IGF-I-/- mice were GF dependent, similar to C/EBPβ-deficient cells. Forced expression of either C/EBPβ or IGF-I in C/EBPβ -/- bone marrow cells restored Myc/Raf-induced transformation and permitted neoplastic growth without exogenous GFs. Thus, our findings demonstrate that C/EBPβ is essential for oncogenic transformation of macrophages and functions at least in part by regulating expression of the survival factor IGF-I.

UR - http://www.scopus.com/inward/record.url?scp=1842609866&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1842609866&partnerID=8YFLogxK

U2 - 10.1128/MCB.24.8.3238-3250.2004

DO - 10.1128/MCB.24.8.3238-3250.2004

M3 - Article

VL - 24

SP - 3238

EP - 3250

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 8

ER -