TGF-beta Induces Growth Arrest in Burkitt Lymphoma Cells via Transcriptional Repression of E2F-1

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    Abstract

    Transforming growth factor-beta(TGF-beta) is a potent regulator of tissue homeostasis and can act as both a tumor suppressor and a tumor promoter. The ability to induce cell cycle arrest is a major component of the tumor suppressor function of TGF-beta. Lung, mammary, and skin epithelial cells exhibit a common minimal cytostatic program in response to TGF-beta signaling involving the repression of the growth-promoting factors c-MYC, Id1, Id2, and Id3. Loss of c-MYC expression is a pivotal event in this process, resulting in derepression of the cyclin-dependent kinase inhibitors CDKN1A (p21) and CDKN2B (p15) and ultimately leading to growth arrest. It is not clear, however, which responses are necessary for TGF-beta-mediated growth arrest in other cell types. Here, in human Burkitt lymphoma cells transformed by deregulated c-MYC expression, we demonstrate that efficient TGF-beta-induced cytostasis can occur despite both maintenance of c-MYC levels and a lack of p21 and p15 induction. TGF-beta treatment also results in induction, rather than repression, of Id1 and Id2 expression. In this context, growth arrest correlates with transcriptional repression of E2F-1, and overexpression of E2F-1 in Burkitt lymphoma cells largely overcomes the TGF-beta-mediated G(1) arrest phenotype. These data indicate that deregulation of c-MYC in lymphoma cells does not overcome the tumor suppressor function of TGF-beta and that repression of E2F-1 transcription is sufficient for the efficient induction of cytostasis.

    Original languageEnglish
    Pages (from-to)1435-1442
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume284
    Issue number3
    DOIs
    Publication statusPublished - 16 Jan 2009

    Keywords

    • CDK INHIBITOR P15(INK4B)
    • EPSTEIN-BARR-VIRUS
    • HUMAN B-CELLS
    • C-MYC
    • UP-REGULATION
    • CYCLE ARREST
    • TUMOR-SUPPRESSOR
    • EPITHELIAL-CELLS
    • CANCER-CELLS
    • G(1) ARREST

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