RETRACTED ARTICLE: Cyclin-dependent kinase 4/6 activity is a critical determinant of pre-replication complex assembly

Braden, Wesley A.; McClendon, A. Kathleen; Knudsen, Erik S.

doi:10.1038/onc.2008.319

Cited by 29 publications

(28 citation statements)

References 57 publications

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“…CDK6 was demonstrated to be often overexpressed in lung tumors (22). CDK6 activity promotes expression of cell cycle regulators and assembly of the prereplication complex (23), and pharmacologic inhibition of CDK6 induces cell cycle arrest (24). NEK7, a centrosomal kinase, regulates proper spindle assembly and mitotic progression (25).…”

Section: Kdm2a Indirectly Up-regulates Expression Of Cell Cycle-assocmentioning

confidence: 99%

Transcriptional Repression of Histone Deacetylase 3 by the Histone Demethylase KDM2A Is Coupled to Tumorigenicity of Lung Cancer Cells

Dhar

Alam

et al. 2014

Journal of Biological Chemistry

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Background: Overexpression of the epigenetic repressor KDM2A promotes lung tumorigenesis. Results: Transcriptional inhibition of HDAC3 expression by KDM2A releases cell cycle and proinvasive genes from HDAC3-mediated repression and positively regulates cell proliferation and invasiveness. Conclusion: KDM2A-mediated repression of HDAC3 is linked to KDM2A-promoted tumorigenicity. Significance: Our findings provide a novel epigenetic insight into how KDM2A promotes lung tumorigenesis and have implications for therapeutic intervention.

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Section: Kdm2a Indirectly Up-regulates Expression Of Cell Cycle-assocmentioning

confidence: 99%

Transcriptional Repression of Histone Deacetylase 3 by the Histone Demethylase KDM2A Is Coupled to Tumorigenicity of Lung Cancer Cells

Dhar

Alam

et al. 2014

Journal of Biological Chemistry

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“…31,32 In addition, E2F1 regulates a number of genes involved in DNA repair, chromosomal stability, and apoptosis. 33,34 Importantly, E2F1 induces transcription of p53, 35 whereas p53 represses the activity of E2F1, thus forming a negative feedback loop.…”

Section: 21mentioning

confidence: 99%

“…30 Cdk2/cyclin E and Cdk4/6 partnered with various forms of cyclin D are the principal kinases required for replication of DNA. 31,32 In addition, E2F1 regulates a number of genes involved in DNA repair, chromosomal stability, and apoptosis. 33,34 Importantly, E2F1 induces transcription of p53, 35 whereas p53 represses the activity of E2F1, thus forming a negative feedback loop.…”

mentioning

confidence: 99%

KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress

et al. 2014

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During the recent years lysine methyltransferase Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) has emerged as an important regulator of different transcription factors. In this study, we report a novel function for Set7/9 as a critical co-activator of E2 promoter-binding factor 1 (E2F1)-dependent transcription in response to DNA damage. By means of various biochemical, cell biology, and bioinformatics approaches, we uncovered that cell-cycle progression through the G1/S checkpoint of tumour cells upon DNA damage is defined by the threshold of expression of both E2F1 and Set7/9. The latter affects the activity of E2F1 by indirectly modulating histone modifications in the promoters of E2F1-dependent genes. Moreover, Set7/9 differentially affects E2F1 transcription targets: it promotes cell proliferation via expression of the CCNE1 gene and represses apoptosis by inhibiting the TP73 gene. Our biochemical screening of the panel of lung tumour cell lines suggests that these two factors are critically important for transcriptional upregulation of the CCNE1 gene product and hence successful progression through cell cycle. These findings identify Set7/9 as a potential biomarker in tumour cells with overexpressed E2F1 activity. Cell Death and Differentiation (2014) 21, 1889-1899; doi:10.1038/cdd.2014.108; published online 15 August 2014Lysine methylation of non-histone proteins has recently emerged as a novel regulatory mechanism to control protein functions. 1-4Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) is a founding member of the family of non-chromatin lysine methyltransferases (KMTases). Set7/9 was initially identified as a monomethylase of histone H3 lysine 4 (H3K4) in vitro. 4,5However, we and others showed that the recombinant Set7/9 failed to target nucleosomes for methylation, [6][7][8] suggesting that Set7/9 functions as a factor-specific KMTase. There have been several non-histone proteins reported as the substrates for Set7/9, including TAF10 (TATA box binding protein (TBP)-associated factor, 30 kDa), 9 oestrogen receptor a (ERa), 10 RelA, 11 PCAF (P300/CBP-associated factor), 12 Stat3,13 Yap, 14 and Suv39h1. 15 However, in most cases the functional significance of this methylation is still not clear. The beststudied targets of Set7/9-mediated methylation are p53 16 and E2 promoter-binding factor 1 (E2F1), 17 transcription factors involved in regulation of DNA damage response (DDR).In response to genotoxic stress cancer cells undergo cell-cycle arrest either in G1/S or G2/M or in both checkpoints. The presence of intact p53 in cancer cells mediates transient G1/S checkpoint arrest, 18,19 which allows cells to repair the damaged DNA before replication or, if the amount of damage is insurmountable, drives cells into apoptosis. 20,21On the contrary, the activity of the E2F family transcription factors, especially E2F1, drives cells from the G1/S block to mitosis. 22,23 Transcriptional activity of E2F1, in turn, is repressed by the retin...

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“…The BrdU pulse was 4 h. For cell cycle analysis in MCF7 cells, flow cytometry was carried out as described previously (6). Prior to being harvested, cells were pulsed with BrdU (GE Healthcare Life Sciences) for 1 h and then were trypsinized and washed with PBS.…”

Section: Creert2mentioning

confidence: 99%

Regulation of RB Transcription In Vivo by RB Family Members

Burkhart¹,

Ngai²,

Roake³

et al. 2010

Molecular and Cellular Biology

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In cancer cells, the retinoblastoma tumor suppressor RB is directly inactivated by mutation in the RB gene or functionally inhibited by abnormal activation of cyclin-dependent kinase activity. While variations in RB levels may also provide an important means of controlling RB function in both normal and cancer cells, little is known about the mechanisms regulating RB transcription. Here we show that members of the RB and E2F families bind directly to the RB promoter. To investigate how the RB/E2F pathway may regulate Rb transcription, we generated reporter mice carrying an eGFP transgene inserted into a bacterial artificial chromosome containing most of the Rb gene. Expression of eGFP largely parallels that of Rb in transgenic embryos and adult mice. Using these reporter mice and mutant alleles for Rb, p107, and p130, we found that RB family members modulate Rb transcription in specific cell populations in vivo and in culture. Interestingly, while Rb is a target of the RB/E2F pathway in mouse and human cells, Rb expression does not strictly correlate with the cell cycle status of these cells. These experiments identify novel regulatory feedback mechanisms within the RB pathway in mammalian cells.The RB tumor suppressor gene was first identified through its direct mutation or deletion in human retinoblastoma. The RB protein is thought to function largely as a transcriptional cofactor that can repress or potentiate the functions of numerous transcription factors, affecting the expression of a broad number of target genes. Since its initial discovery, RB function has been demonstrated to be inactivated in virtually all human cancers through a variety of mechanisms. In particular, in addition to direct mutation events in the RB gene, the RB protein is often functionally inactivated by phosphorylation in tumor cells with constitutive activation of cyclin/Cdk complexes (44,55). RB inactivation through reduced transcription may also participate in the development of cancer (4, 41); surprisingly, however, little is known about the mechanisms regulating RB transcription in normal and tumor cells.Interestingly, the RB promoter contains a conserved binding site for the E2F transcription factors, some of which are direct partners of RB and key downstream mediators of RB (9). Increasing evidence suggests that this site may contribute to the regulation of RB transcription. For instance, overexpression of E2F1 can activate RB transcription, which may contribute to the variations in RB mRNA levels during cell cycle progression that are observed in some contexts (30, 43) but not in others (5,13,20). In addition, methylation of the E2F site in the RB promoter is sufficient to recruit repressor complexes to inhibit RB transcription (15). Accordingly, reporter assays show that mutation of the E2F site in the RB promoter leads to an absence of RB repression (33). Furthermore, mutation of the E2F (and Sp1) sites in the mouse Rb promoter in transgenic mice has revealed the importance of these sites for Rb expression in vivo (1).Togeth...

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RETRACTED ARTICLE: Cyclin-dependent kinase 4/6 activity is a critical determinant of pre-replication complex assembly

Cited by 29 publications

References 57 publications

Transcriptional Repression of Histone Deacetylase 3 by the Histone Demethylase KDM2A Is Coupled to Tumorigenicity of Lung Cancer Cells

Transcriptional Repression of Histone Deacetylase 3 by the Histone Demethylase KDM2A Is Coupled to Tumorigenicity of Lung Cancer Cells

KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress

Regulation of RB Transcription In Vivo by RB Family Members

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