Inactivation of E2F3 results in centrosome amplification

Saavedra, Harold I.; Maiti, Baidehi; Timmers, Cynthia; Altura, Rachel A.; Tokuyama, Yukari; Fukasawa, Kenji; Leone, Gustavo

doi:10.1016/s1535-6108(03)00083-7

Cited by 71 publications

(83 citation statements)

References 65 publications

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“…Interestingly, in the absence of cooperating hits, the same growthpromoting mutations found in cancers typically trigger these events in primary cells (30). For example, overexpression of E2Fs in primary cells also leads to p53-dependent apoptosis, polyploidy, and growth arrest (19,31,32).…”

Section: Discussionmentioning

confidence: 99%

Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation

Isakoff

Sansam

Tamayo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

199

208

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Snf5 (Ini1͞Baf47͞Smarcb1), a core member of the Swi͞Snf chromatin remodeling complex, is a potent tumor suppressor whose mechanism of action is largely unknown. Biallelic loss of Snf5 leads to the onset of aggressive cancers in both humans and mice. We have developed an innovative and widely applicable analytical technique for cross-species validation of cancer models and show that the gene expression profiles of our Snf5 murine models closely resemble those of human Snf5-deficient rhabdoid tumors. We exploit this system to produce what we believe to be the first report documenting the effects on gene expression of inactivating a Swi͞Snf subunit in normal mammalian cells and to identify the transcriptional pathways regulated by Snf5. We demonstrate that the tumor suppressor activity of Snf5 depends on its regulation of cell cycle progression; Snf5 inactivation leads to aberrant upregulation of E2F targets and increased levels of p53 that are accompanied by apoptosis, polyploidy, and growth arrest. Further, conditional mouse models demonstrate that inactivation of p16Ink4a or Rb (retinoblastoma) does not accelerate tumor formation in Snf5 conditional mice, whereas mutation of p53 leads to a dramatic acceleration of tumor formation.chromatin remodeling ͉ gene expression analysis ͉ mouse models ͉ Swi͞Snf

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Section: Discussionmentioning

confidence: 99%

Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation

Isakoff

Sansam

Tamayo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

199

208

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“…21 This may be related to the finding that E2F3 deficiency leads to centrosome amplification and genetic instability. 35 Inactivation of E2F3 has not www.landesbioscience.com…”

Section: Discussionmentioning

confidence: 99%

E2F3a Stimulates Proliferation, p53-Independent Apoptosis and Carcinogenesis in a Transgenic Mouse Model

2005

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=2307 KEY WORDSE2F3, cell cycle, transgenic mouse, apoptosis, skin carcinogenesis ABBREVIATIONS RbRetinoblastoma ABSTRACTMutation or inactivation of the retinoblastoma (Rb) tumor suppressor occurs in most human tumors and results in the deregulation of several members of the E2F family of transcription factors. Among the E2F family, E2F3 has been implicated as a key regulator of cell proliferation and E2F3 gene amplification and overexpression is detected in some human tumors. To study the role of E2F3 in tumor development, we established a transgenic mouse model expressing E2F3a in a number of epithelial tissues via a keratin 5 (K5) promoter. Transgenic expression of E2F3a leads to hyperproliferation, hyperplasia and increased levels of p53-independent apoptosis in transgenic epidermis. Consistent with data from human cancers, the E2F3a transgene is found to have a weak oncogenic activity on its own and to significantly enhance the response to a skin carcinogenesis protocol. The phenotype of K5 E2F3a transgenic mice is distinct from similar transgenic mice expressing E2F1 or E2F4. In particular, E2F3a has a unique apoptotic activity and lacks the tumor suppressive property of E2F1 in this model system.

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“…12 and 14. Removal of the E2F3 alleles of E2F1 Ϫ/Ϫ E2F2 Ϫ/Ϫ E2F3 f/f MEFs (15,16) was achieved by infecting cells with retrovirus particles encoding a ''self-excising'' CRE recombinase (36) and was used for ChIP 2 days later. Chromatin was immunoprecipitated with histone tail-specific modifications antibodies (#06942, #07213, #07214, #07215, #07404, #07080, #07405, and #07212; Upstate Biotechnology, Lake Placid, NY), ␣-CARM1 (#07080; Upstate Biotechnology), ␣-PRMT1 (AB7027; Abcam, Cambridge, MA), ␣-PRMT5 [mix of BD#611539 (Becton Dickinson, Erembodegem, Belgium) and #07405 (Upstate Biotechnology)], ␣-SP1 (sc59; Santa Cruz Biotechnology, Santa Cruz, CA) and anti-ACTR/AIB1 (BD#611105; Becton Dickinson).…”

Section: Methodsmentioning

confidence: 99%

“…CCNE1 gene transcription is undetectable in G 0 and G 1 phases of the cell cycle, whereas it rises sharply during a narrow window of time that precedes each entry into S phase. Several pieces of evidence suggest that the periodic association of activators E2Fs-and E2F-pocket protein complexes regulate CCNE1 gene expression (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). E2F complexes bound to this gene were found to recruit chromatin modifiers, including members of the SNF2-like helicase family, type I histone deacetylases, the acetyltransferase CBP͞p300, the lysine methyl transferase SUVAR39H1, and the protein arginine N-methyltransferase (PRMT) 5 (7, 9-14, 17, 18), suggesting that they foster periodic chromatin remodeling of the CCNE1 promoter region (11,12,14).…”

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confidence: 99%

Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin E1 gene

Messaoudi

Fabbrizio

Rodrı́guez³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

164

153

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The Cyclin E1 gene (CCNE1) is an ideal model to explore the mechanisms that control the transcription of cell cycle-regulated genes whose expression rises transiently before entry into S phase. E2F-dependent regulation of the CCNE1 promoter was shown to correlate with changes in the level of H3-K9 acetylation͞methyl-ation of nucleosomal histones positioned at the transcriptional start site region. Here we show that, upon growth stimulation, the same region is subject to variations of H3-R17 and H3-R26 methylation that correlate with the recruitment of coactivator-associated arginine methyltransferase 1 (CARM1) onto the CCNE1 and DHFR promoters. Accordingly, CARM1-deficient cells lack these modifications and present lowered levels and altered kinetics of CCNE1 and DHFR mRNA expression. Consistently, reporter gene assays demonstrate that CARM1 functions as a transcriptional coactivator for their E2F1͞DP1-stimulated expression. CARM1 recruitment at the CCNE1 gene requires activator E2Fs and ACTR, a member of the p160 coactivator family that is frequently overexpressed in human breast cancer. Finally, we show that grade-3 breast tumors present coelevated mRNA levels of ACTR and CARM1, along with their transcriptional target CCNE1. All together, our results indicate that CARM1 is an important regulator of the CCNE1 gene.ACTR ͉ CCNE1 ͉ histone ͉ arginine methylation ͉ breast tumor C yclin E1 (CCNE1) protein and mRNA levels are tightly regulated as an endpoint of several regulatory pathways that are critical for growth control and frequently altered in cancer cells (1, 2). CCNE1 gene transcription is undetectable in G 0 and G 1 phases of the cell cycle, whereas it rises sharply during a narrow window of time that precedes each entry into S phase. Several pieces of evidence suggest that the periodic association of activators E2Fs-and E2F-pocket protein complexes regulate CCNE1 gene expression (3-18). E2F complexes bound to this gene were found to recruit chromatin modifiers, including members of the SNF2-like helicase family, type I histone deacetylases, the acetyltransferase CBP͞p300, the lysine methyl transferase SUVAR39H1, and the protein arginine N-methyltransferase (PRMT) 5 (7, 9-14, 17, 18), suggesting that they foster periodic chromatin remodeling of the CCNE1 promoter region (11,12,14). Notably, repression of the CCNE1 gene in G 0 -G 1 correlates with the methylation of H3-K9 and H4-R3 on a single nucleosome positioned at the transcriptional start site (11)(12)(13)(14). Conversely, the late G 1 activation of the CCNE1 gene correlates with decreased H3-K9 methylation and with enhanced H3͞H4 acetylation of the same chromatin region (11)(12)(13)(14). Here, we reveal that this CCNE1 proximal promoter region is targeted by another histone arginine methyl-transferase, the type I enzyme PRMT4 [coactivator-associated arginine methyltransferase (CARM1)] (19-25). PRMT4͞CARM1 was initially described as a transcriptional coactivator of the p160 family of nuclear receptor-associated factors (Src-1͞NCoA1, GRIP1͞TIF2͞Src-2͞ NC...

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Inactivation of E2F3 results in centrosome amplification

Cited by 71 publications

References 65 publications

Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation

Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation

E2F3a Stimulates Proliferation, p53-Independent Apoptosis and Carcinogenesis in a Transgenic Mouse Model

Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin E1 gene

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