Feedback regulation between atypical E2Fs and
            <scp>APC</scp>
            /
            <scp>
              C
              <sup>C</sup>
            </scp>
            <sup>dh1</sup>
            coordinates cell cycle progression

Boekhout, Michiel; Yuan, Ruixue; Wondergem, Annelotte P.; Segeren, Hendrika A.; Liere, Elsbeth A. van; Awol, Nesibu; Jansen, Imke; Wolthuis, Rob M. F.; Bruin, Alain de; Westendorp, Bart

doi:10.15252/embr.201540984

Cited by 28 publications

(12 citation statements)

References 52 publications

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“…Further investigations are required to examine how and when E2Fs are degraded, but studies from our group and others provide evidence that atypical E2Fs are degraded by the APC/C Cdh1 complex. 43 , 44 These findings might open new avenues for therapeutic approaches to inhibit abundant E2F activity during tumorigenesis. Future studies are required to investigate how the activity of activator E2Fs and atypical E2Fs can be optimally manipulated to inhibit tumor growth for different cancer types.…”

Section: Discussionmentioning

confidence: 98%

Synergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer

et al. 2016

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E2F transcription factors are important regulators of the cell cycle, and unrestrained activation of E2F-dependent transcription is considered to be an important driver of tumor formation and progression. Although highly expressed in normal skin and skin cancer, the role of the atypical E2Fs, E2F7 and E2F8, in keratinocyte homeostasis, regeneration and tumorigenesis is unknown. Surprisingly, keratinocyte-specific deletion of E2F7 and E2F8 in mice did not interfere with skin development and wound healing. However, the rate for successful isolation and establishment of E2f7/8-deficient primary keratinocyte cultures was much higher than for wild-type keratinocytes. Moreover, E2f7/8-deficient primary keratinocytes proliferate more efficiently under stress conditions, such as low/high confluence or DNA damage. Application of in vivo stress using the DMBA/TPA skin carcinogenesis protocol revealed that combined inactivation of E2f7/8 enhanced tumorigenesis and accelerated malignant progression. Loss of atypical E2Fs resulted in increased expression of E2F target genes, including E2f1. Additional loss of E2f1 did not rescue, but worsened skin tumorigenesis. We show that loss of E2F7/8 triggers apoptosis via induction of E2F1 in response to stress, indicating that the tumor-promoting effect of E2F7/8 inactivation can be partially compensated via E2F1-dependent apoptosis. Importantly, E2F7/8 repressed a large set of E2F target genes that are highly expressed in human patients with skin cancer. Together, our studies demonstrate that atypical E2Fs act as tumor suppressors, most likely via transcriptional repression of cell cycle genes in response to stress.

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Section: Discussionmentioning

confidence: 98%

Synergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer

et al. 2016

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“…Besides transcriptional mechanisms, post-transcriptional regulation is known to play an important role in the temporal control of E2F-dependent transcription. Ubiquitin-mediated protein degradation has been proposed to regulate the activity of several E2Fs in vitro (Boekhout et al, 2016; Marti et al, 1999; Ping et al, 2012). Whereas mRNA levels of E2F activators and atypical repressors increased similarly as cells moved from G 0 to G 1 , S-G 2 , and M, peak protein levels of E2F3A and E2F8 were clearly temporally distinct during the cell cycle, with only a partial overlap during S phase.…”

Section: Discussionmentioning

confidence: 99%

Two Distinct E2F Transcriptional Modules Drive Cell Cycles and Differentiation

et al. 2019

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Graphical Abstract Highlights d E2F expression during cell division, differentiation, and quiescence is measured in vivo d E2F3A, E2F8, and E2F4 accumulate sequentially in the nucleus of cycling cells d E2F3A-4 nuclear accumulation controls gene expression during cell-cycle exit d Deep learning tools are applied to nuclear segmentation of complex mammalian tissues In Brief The study of E2Fs in vivo has been challenging. Cuitiñ o et al. reconstruct the spatiotemporal expression of E2F activators (E2F3A) and canonical (E2F4) and atypical (E2F8) repressors during the mammalian cell cycle and propose that orchestrated accumulation of different E2F combinations control gene expression in proliferating (E2F3A-8-4) and differentiating (E2F3A-4) cells. SUMMARYOrchestrating cell-cycle-dependent mRNA oscillations is critical to cell proliferation in multicellular organisms. Even though our understanding of cellcycle-regulated transcription has improved significantly over the last three decades, the mechanisms remain untested in vivo. Unbiased transcriptomic profiling of G 0 , G 1 -S, and S-G 2 -M sorted cells from FUCCI mouse embryos suggested a central role for E2Fs in the control of cell-cycle-dependent gene expression. The analysis of gene expression and E2F-tagged knockin mice with tissue imaging and deep-learning tools suggested that post-transcriptional mechanisms universally coordinate the nuclear accumulation of E2F activators (E2F3A) and canonical (E2F4) and atypical (E2F8) repressors during the cell cycle in vivo. In summary, we mapped the spatiotemporal expression of sentinel E2F activators and canonical and atypical repressors at the singlecell level in vivo and propose that two distinct E2F modules relay the control of gene expression in cells actively cycling (E2F3A-8-4) and exiting the cycle (E2F3A-4) during mammalian development.

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“…In exponentially proliferating cells, E2F1 is targeted for degradation by APC/C Cdc20 during prometaphase, and by APC/C Cdh1 in the late M and early G1 phases [ 22 , 24 ]. APC/C Cdh1 also regulates the stability of E2F3, E2F7 and E2F8 during normal cell cycle progression in a variety of cell types [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

CDH1 regulates E2F1 degradation in response to differentiation signals in keratinocytes

Singh

Dagnino

2016

Oncotarget

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The E2F1 transcription factor plays key roles in skin homeostasis. In the epidermis, E2F1 expression is essential for normal proliferation of undifferentiated keratinocytes, regeneration after injury and DNA repair following UV radiation-induced photodamage. Abnormal E2F1 expression promotes nonmelanoma skin carcinoma. In addition, E2F1 must be downregulated for proper keratinocyte differentiation, but the relevant mechanisms involved remain poorly understood. We show that differentiation signals induce a series of post-translational modifications in E2F1 that are jointly required for its downregulation. Analysis of the structural determinants that govern these processes revealed a central role for S403 and T433. In particular, substitution of these two amino acid residues with non-phosphorylatable alanine (E2F1 ST/A) interferes with E2F1 nuclear export, K11- and K48-linked polyubiquitylation and degradation in differentiated keratinocytes. In contrast, replacement of S403 and T433 with phosphomimetic aspartic acid to generate a pseudophosphorylated E2F1 mutant protein (E2F1 ST/D) generates a protein that is regulated in a manner indistinguishable from that of wild type E2F1. Cdh1 is an activating cofactor that interacts with the anaphase-promoting complex/cyclosome (APC/C) ubiquitin E3 ligase, promoting proteasomal degradation of various substrates. We found that Cdh1 associates with E2F1 in keratinocytes. Inhibition or RNAi-mediated silencing of Cdh1 prevents E2F1 degradation in response to differentiation signals. Our results reveal novel regulatory mechanisms that jointly modulate post-translational modifications and downregulation of E2F1, which are necessary for proper epidermal keratinocyte differentiation.

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Feedback regulation between atypical E2Fs and APC / C ^C ^dh1 coordinates cell cycle progression

Cited by 28 publications

References 52 publications

Synergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer

Synergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer

Two Distinct E2F Transcriptional Modules Drive Cell Cycles and Differentiation

CDH1 regulates E2F1 degradation in response to differentiation signals in keratinocytes

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Feedback regulation between atypical E2Fs and APC / C C dh1 coordinates cell cycle progression

Cited by 28 publications

References 52 publications

Synergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer

Synergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer

Two Distinct E2F Transcriptional Modules Drive Cell Cycles and Differentiation

CDH1 regulates E2F1 degradation in response to differentiation signals in keratinocytes

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Feedback regulation between atypical E2Fs and APC / C ^C ^dh1 coordinates cell cycle progression