Post-Transcriptional Regulation of E2F Transcription Factors: Fine-Tuning DNA Repair, Cell Cycle Progression and Survival in Development & Disease

ABSTRACT Independent of its antiapoptotic function, Bcl-2 can, through an undetermined mechanism, retard entry into the cell cycle. Cell cycle progression requires the phosphorylation by cyclin-dependent kinases (Cdks) of retinoblastoma protein (pRB) family members to free E2F transcription factors. We have explored whether retarded cycle entry is mediated by the Cdk inhibitor p27 or the pRB family. In quiescent fibroblasts, enforced Bcl-2 expression elevated levels of both p27 and the pRB relative p130. Bcl-2 still slowed G1 progression in cells deficient in pRB but not in those lacking p27 or p130. Hence, pRB is not required, but both p27 and p130 are essential mediators. The ability of p130 to form repressive complexes with E2F4 is implicated, because the retardation by Bcl-2 was accentuated by coexpressed E2F4. A plausible relevant target of p130/E2F4 is the E2F1 gene, because Bcl-2 expression delayed E2F1 accumulation during G1 progression and overexpression of E2F1 overrode the Bcl-2 inhibition. Hence, Bcl-2 appears to retard cell cycle entry by increasing p27 and p130 levels and maintaining repressive complexes of p130 with E2F4, perhaps to delay E2F1 expression.

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IKK/NF-κB signaling pathway inhibits cell-cycle progression by a novel Rb-independent suppression system for E2F transcription factors

Oncogene ◽

10.1038/onc.2008.184 ◽

2008 ◽

Vol 27 (43) ◽

pp. 5696-5705 ◽

Cited By ~ 22

Author(s):

K Araki ◽

K Kawauchi ◽

N Tanaka

Keyword(s):

Cell Cycle ◽

Transcription Factors ◽

Signaling Pathway ◽

Cell Cycle Progression ◽

Cycle Progression ◽

E2f Transcription Factors ◽

Suppression System

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Faculty Opinions recommendation of E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1005538.71460 ◽

2002 ◽

Author(s):

Michael Meisterernst

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Cell Cycle Progression ◽

Cycle Progression

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IRX3/5 regulate mitotic chromatid segregation and limb bud shape

Development ◽

10.1242/dev.180042 ◽

2020 ◽

Vol 147 (19) ◽

pp. dev180042

Author(s):

Hirotaka Tao ◽

Jean-Philippe Lambert ◽

Theodora M. Yung ◽

Min Zhu ◽

Noah A. Hahn ◽

...

Keyword(s):

Cell Cycle ◽

Transcriptional Regulation ◽

Cell Division ◽

Pattern Formation ◽

Cell Cycle Progression ◽

Limb Bud ◽

Cycle Progression ◽

Chromatid Segregation ◽

Skeletal Pattern

ABSTRACTPattern formation is influenced by transcriptional regulation as well as by morphogenetic mechanisms that shape organ primordia, although factors that link these processes remain under-appreciated. Here we show that, apart from their established transcriptional roles in pattern formation, IRX3/5 help to shape the limb bud primordium by promoting the separation and intercalation of dividing mesodermal cells. Surprisingly, IRX3/5 are required for appropriate cell cycle progression and chromatid segregation during mitosis, possibly in a nontranscriptional manner. IRX3/5 associate with, promote the abundance of, and share overlapping functions with co-regulators of cell division such as the cohesin subunits SMC1, SMC3, NIPBL and CUX1. The findings imply that IRX3/5 coordinate early limb bud morphogenesis with skeletal pattern formation.

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Abstract C46: DNA damage-induced autophagy is required for efficient DNA repair and cell cycle progression

Cancer Research ◽

10.1158/1538-7445.prca2012-c46 ◽

2012 ◽

Vol 72 (4 Supplement) ◽

pp. C46-C46

Author(s):

Kamini Singh ◽

Sayer R. Al-Harbi ◽

Akwasi Agyeman ◽

Janet A. Houghton ◽

Warren D. Heston ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Repair ◽

Cell Cycle Progression ◽

Cycle Progression

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B Lymphocytes Differentially Use the Rel and Nuclear Factor κB1 (NF-κB1) Transcription Factors to Regulate Cell Cycle Progression and Apoptosis in Quiescent and Mitogen-activated Cells

Journal of Experimental Medicine ◽

10.1084/jem.187.5.663 ◽

1998 ◽

Vol 187 (5) ◽

pp. 663-674 ◽

Cited By ~ 169

Author(s):

Raelene J. Grumont ◽

Ian J. Rourke ◽

Lorraine A. O'Reilly ◽

Andreas Strasser ◽

Kensuke Miyake ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Transcription Factors ◽

B Cells ◽

B Cell ◽

B Lymphocytes ◽

Cell Cycle Progression ◽

Nuclear Factor ◽

Cycle Progression ◽

Regulate Cell Cycle Progression

Rel and nuclear factor (NF)-κB1, two members of the Rel/NF-κB transcription factor family, are essential for mitogen-induced B cell proliferation. Using mice with inactivated Rel or NF-κB1 genes, we show that these transcription factors differentially regulate cell cycle progression and apoptosis in B lymphocytes. Consistent with an increased rate of mature B cell turnover in naive nfkb1−/− mice, the level of apoptosis in cultures of quiescent nfkb1−/−, but not c-rel−/−, B cells is higher. The failure of c-rel−/− or nfkb1−/− B cells to proliferate in response to particular mitogens coincides with a cell cycle block early in G1 and elevated cell death. Expression of a bcl-2 transgene prevents apoptosis in resting and activated c-rel−/− and nfkb1−/− B cells, but does not overcome the block in cell cycle progression, suggesting that the impaired proliferation is not simply a consequence of apoptosis and that Rel/NF-κB proteins regulate cell survival and cell cycle control through independent mechanisms. In contrast to certain B lymphoma cell lines in which mitogen-induced cell death can result from Rel/NF-κB–dependent downregulation of c-myc, expression of c-myc is normal in resting and stimulated c-rel−/− B cells, indicating that target gene(s) regulated by Rel that are important for preventing apoptosis may differ in normal and immortalized B cells. Collectively, these results are the first to demonstrate that in normal B cells, NF-κB1 regulates survival of cells in G0, whereas mitogenic activation induced by distinct stimuli requires different Rel/NF-κB factors to control cell cycle progression and prevent apoptosis.

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Chronic Myeloid Leukemia with Variant t(9;22) Shows Dysregulated Expression of Genes Included in Pivotal Cellular Pathways

Blood ◽

10.1182/blood.v120.21.1674.1674 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1674-1674

Author(s):

Francesco Albano ◽

Luisa Anelli ◽

Antonella Zagaria ◽

Nicoletta Coccaro ◽

Luciana Impera ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Dna Repair ◽

Chronic Myeloid Leukemia ◽

Protein Degradation ◽

Myeloid Leukemia ◽

Cell Cycle Progression ◽

Molecular Response ◽

Cycle Progression ◽

Functional Relationships

Abstract Abstract 1674 The t(9;22)(q34;q11) generating the Philadelphia chromosome and the BCR/ABL1 fusion gene represents the cytogenetic hallmark of chronic myeloid leukemia (CML). About 5–10% of CML cases show variant translocations with the involvement of other chromosomes in addition to chromosomes 9 and 22. The greater frequency of occurrence of genomic microdeletions proximally to ABL1 or distally to BCR has been reported in CML cases with variant translocations (30–40%) than in cases with a classic t(9;22) (10–18%). The prognostic significance of variant t(9;22) was unclear and debated in the pre-imatinib era, whereas recent studies of large CML series showed that the presence of variant translocations has no impact on the cytogenetic and molecular response or on prognosis (Marzocchi et al. Blood 2011,117:6793-800). However, the molecular bases of differences between CML patients with classic and variant t(9;22) have never been elucidated. Here we report a gene expression profile analysis of 8 CML cases with variant t(9;22) and 12 patients with a classic t(9;22). RNA samples were extracted from bone marrow cells and hybridized on the Agilent SurePrint G3 Human GE 8×60K Microarray slide (Agilent Technologies). Ingenuity Pathways Analysis (IPA, www.ingenuity.com) software was used to provide an accurate biological and statistical analysis of microarray experimental data revealing functional relationships among the identified genes. Gene expression analysis identified a 59 gene set able to distinguish the two CML subsets. These genes are mostly involved in the development of the hematological system and in the occurrence of hematological diseases. Forty-five out of 59 (76%) genes were up-regulated, causing the probable activation of different molecular mechanisms such as cellular responses to stimuli, protein degradation, DNA repair, cell cycle progression. IPA analysis revealed that most of the dysregulated genes are included in a network where they are functionally linked to MAPK p38, AKT, and NFKB. Moreover, several genes play a role in cytoskeleton organization (WIPF1), in signal transduction and cell cycle progression (TRIB1, PDE4B, PTK2B, PLK3), in regulation of apoptosis (ZFAND5, STK17B), and in protein degradation (ZFAND5, SNRPG). On the contrary, among the downregulated genes, 5 (BCDIN3D, TMEM68, HILPDA, TMEM68, and C17orf61) establish direct interactions with ubiquitin C (UBC), a crucial gene involved in different intracellular mechanisms such as protein degradation, DNA repair, cell cycle regulation, and the regulation of other signaling pathways. In conclusion, gene expression profiling in cases with variant t(9;22) revealed biological differences in this CML subset. Our data show an overall deregulation of genes involved in hematological system development and in cell proliferation signaling pathway. Disclosures: No relevant conflicts of interest to declare.

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