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Heparin-binding epidermal growth factor-like growth factor, a v-Jun target gene, induces oncogenic transformation.

ABSTRACT: Jun is a transcription factor belonging to the activator protein 1 family. A mutated version of Jun (v-Jun) transduced by the avian retrovirus ASV17 induces oncogenic transformation in avian cell cultures and sarcomas in young galliform birds. The oncogenicity of Jun probably results from transcriptional deregulation of v-Jun-responsive target genes. Here we describe the identification and characterization of a growth-related v-Jun target, a homolog of heparin-binding epidermal growth factor-like growth factor (HB-EGF). HB-EGF is strongly expressed in chicken embryo fibroblasts (CEF) transformed by v-Jun. HB-EGF expression is not detectable or is marginal in nontransformed CEF. Using a hormone-inducible Jun-estrogen receptor chimera, we found that HB-EGF expression is correlated with v-Jun activity. In this system, induction of v-Jun is followed within 1 hr by elevated levels of HB-EGF. In CEF infected with various Jun mutants, HB-EGF expression is correlated with the oncogenic potency of the mutant. Constitutive expression of HB-EGF conveys to CEF the ability to grow in soft agar and to form multilayered foci of transformed cells on a solid substrate. These observations suggest that HB-EGF is an effector of Jun-induced oncogenic transformation.

SUBMITTER: Fu Sl

PROVIDER: S-EPMC21926 | biostudies-literature | 1999 May

REPOSITORIES: biostudies-literature

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Heparin-binding epidermal growth factor-like growth factor, a v-Jun target gene, induces oncogenic transformation.

Fu S l Sl Bottoli I I Goller M M Vogt P K PK

Proceedings of the National Academy of Sciences of the United States of America 19990501 10

Jun is a transcription factor belonging to the activator protein 1 family. A mutated version of Jun (v-Jun) transduced by the avian retrovirus ASV17 induces oncogenic transformation in avian cell cultures and sarcomas in young galliform birds. The oncogenicity of Jun probably results from transcriptional deregulation of v-Jun-responsive target genes. Here we describe the identification and characterization of a growth-related v-Jun target, a homolog of heparin-binding epidermal growth factor-lik ...[more]

PMID: 10318950

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Project description:Products of adipocytes control bone cells and may therefore lead to new anti-osteoporosis therapies. To address this issue we mated mice expressing the primate diphtheria toxin receptor (DTR), which is equivalent to Heparin Binding Epidermal Like Growth Factor (HB-EGF), under control of a Stop-flox cassette, to those expressing adiponectin-Cre (ADQ-Cre). Injected diphtheria toxin (DT) completely eliminates white and brown adipose tissue in these DTRADQ mice and ablates marrow adipocytes. Medullary bone of DTRADQ mice begins to accumulate, due to stimulated osteoblast recruitment and differentiation, within 4 days of injected DT. By 10-14 days of DT administration to DTRADQ mice, trabecular bone has increased 1000%. Two months after fat ablation, cortical thickness has markedly increased as has bone strength. To gain insight into the signaling events by which DT/DTRADQ adipocyte ablation promotes osteogenesis we performed RNAseq analysis of marrow prior to and after 1-3 days of DT injection. This exercise confirms ablation of marrow adipocytes, as adiponectin expression is markedly reduced while enhanced expression of Col1a1 and Col1a2 genes is in keeping with stimulated osteogenesis. RNAseq analysis also indicates that DT/DTRADQ-induced osteogenesis is mediated by the BMPR pathway. For example, there is suppressed genetic expression of the specific BMPR inhibitors, chordin-like1 (CHRDL1) and gremlin1 (GREM1). This adipocyte ablation-mediated increase in bone mass is due to cooperative activation of BMP and EGF receptor signaling as adipocyte-produced inhibitors are suppressed and downstream targets activated or expressed. Medicinal inhibition of either signaling pathway prevents induction of the osteosclerotic phenotype. DTR-induced post-natal osteogenesis does not represent the products of peripheral fat depots and is more likely due to those of marrow adipocytes. Thus, anabolic drugs activating both BMP and EGF receptor signaling may be a means of profoundly increasing bone mass and treating osteoporosis.

Dataset Information

Heparin-binding epidermal growth factor-like growth factor, a v-Jun target gene, induces oncogenic transformation.

Publications

Heparin-binding epidermal growth factor-like growth factor, a v-Jun target gene, induces oncogenic transformation.

Similar Datasets

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