Repression of c-Myc responsive genes in cycling cells causes G1 arrest through reduction of cyclin E/CDK2 kinase activity

Berns, Katrien; Hijmans, E. Marielle; Bernards, René

doi:10.1038/sj.onc.1201280

Cited by 100 publications

(99 citation statements)

References 44 publications

(64 reference statements)

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“…Therefore, we assessed the requirement of Myc transcriptional activity for the apoptotic phenotype observed in U2OS-RbDcdk/Myc cells. For this purpose we transfected these cells with MadMyc (MM), a previously described chimera that antagonizes Myc by inhibiting its transcriptional regulatory function (Berns et al, 1997;Santoni-Rugiu et al, 2000). Consistent with our earlier results (Santoni-Rugiu et al, 2000), MM abolished the massive entry and accumulation of the U2OS-RbDcdk/Myc cells in S phase.…”

Section: Constitutively Active Rb Induces Death Of U2os-myc Cellssupporting

confidence: 80%

E2F activity is essential for survival of Myc-overexpressing human cancer cells

et al. 2002

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Effective cell cycle completion requires both Myc and E2F activities. However, whether these two activities interact to regulate cell survival remains to be tested. Here we have analysed survival of inducible c-Mycoverexpressing cell lines derived from U2OS human osteosarcoma cells, which carry wild-type pRb and p53 and are deficient for p16 and ARF expression. Induced U2OS-Myc cells neither underwent apoptosis spontaneously nor upon reconstitution of the ARF-p53 axis and/or serum-starvation. However, they died massively when concomitantly exposed to inhibitors of E2F activity, including a constitutively active pRb (RbDcdk) mutant, p16, a stable p27 (p27T187A) mutant, a dominant-negative (dn) CDK2, or dnDP-1. Similar apoptotic effect was observed upon down-modulation of endogenous E2Fs through overexpression of E2F binding site oligonucleotides in U2OS-Myc cells, upon expression of RbDcdk or dnDP-1 in the Myc-amplified HL-60 (ARF7; p537) human leukemia cells, and upon cotransfection of Myc and RbDcdk in SAOS-2 (ARF+; p537) human osteosarcoma cells but not in human primary fibroblasts. Consistent with these results, a dnp53 mutant did not abrogate the Myc-induced apoptotic phenotype, which instead strictly depended on caspase-3-like proteases and on Myc transcriptional activity. Our data indicate that in contrast to normal cells, Myc-overexpressing human cancer cells need E2F activity for their survival, regardless of their ARF and p53 status, a notion that may have important implications for antineoplastic treatment strategies.

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Section: Constitutively Active Rb Induces Death Of U2os-myc Cellssupporting

confidence: 80%

E2F activity is essential for survival of Myc-overexpressing human cancer cells

et al. 2002

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“…O'Connell analyzed the c-myc-regulated gene expression patterns and found that cyclin E was responsive to c-myc expression (O'Connell et al, 2003). Inhibition of c-myc in exponentially growing cells leads to G1 arrest through loss of cyclin E-associated kinase activity (Berns et al, 1997), which is essential for G1/S transition (Perez-Roger et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…c-myc directly responds to mitogenic signals that promotes cell-cycle progression (Amati et al, 1998), whereas its deficiency and overexpression alter cell proliferation (Shichiri et al, 1993). It has been shown that c-myc controls cell-cycle progression in G1 phase of mouse embryo fibroblasts (Berns et al, 2000) and NIH3T3 cells (Berns et al, 1997); in S phase of U2OS cells and rat diploid fibroblasts (Santoni-Rugiu et al, 2000); and in G2/M phase of rat fibroblast cell line (Mateyak et al, 1997) and murine NXS2 neuroblastoma cells (Ushmorov et al, 2005). It has also been characterized that constitutive expression of c-myc is low in human embryonic lung fibroblasts (HEL) and high in human lung carcinoma cell line A549 (Robinson et al, 1995).…”

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confidence: 99%

Cyclin a but not cyclin D1 is essential for c‐myc‐modulated cell‐cycle progression

Yang

et al. 2006

Journal Cellular Physiology

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The proto-oncogene c-myc is a key player in cell-cycle regulation and is deregulated in a broad range of human cancers and cell proliferation disorders. Here we reported that overexpression of c-myc in human embryonic lung fibroblasts (HEL) that have low endogenous c-myc enriched S phase cells with increased expression of cyclin D3, E, A, Cdk2, and Cdk4, and decreased expression of p21 and p27. To the opposite, using RNAi to downregulate c-myc expression in A549 cells that have high endogenous c-myc enriched G1 phase cells with decreased expression of cyclin D3, E, A, Cdk2, Cdk4, and increased expression of p21 and p27. We found that cyclin A expression was the most susceptive to changes in c-myc levels and essential in c-myc-modulated cell cycle pathway via co-transfection, however, cyclin D1 showed no change between treated and control groups in either HEL or A549 cells. Our results indicated that upregulation of c-myc expression promotes cell cycling in HEL cells, whereas downregulation of c-myc expression causes G1 phase arrest in A549 cells, and the c-myc-mediated cell-cycle regulation pathway was dependent on cyclin A and involved cyclin D3, E, Cdk2, Cdk4, p21, and p27, but not cyclin D1.

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“…The growth rates were determined in multiple independent experiments from which one representative experiment is shown. (b) Immunoblot analysis of the retrovirally infected polyclonal cell lines, (7): control pBabe-hygro infected Rat1A cells; (+): Rat 1A cells infected with the indicated cDNA in the pBabe-hygro vector, was performed as described (Berns et al, 1997). The following antibodies were used: c-Myc: PAN-Myc (Genosys Biotechnologies, OA-11-802); cyclin D1: H-285 (Santa Cruz, SC-753); cyclin D2: C-17 (SC-181); cyclin E: C-19 (SC-198); E2F-1: C-20 (SC-193); E2F-2: C-20 (SC-633); E2F-3: C-18 (SC-878); Ras: (Transduction laboratories, R 02120); SV40 T antigen: monoclonal 419 (kindly provided by Dr AJ van der Eb); SKP2: a nity puri®ed rabbit antip45 (a kind gift from Dr W Krek).…”

Section: Abstract: C-myc; Cell Proliferation; Cell Cyclementioning

confidence: 99%