Organ Size Control Is Dominant over Rb Family Inactivation to Restrict Proliferation In Vivo

Ehmer, Ursula; Zmoos, Anne-Flore; Auerbach, Raymond K.; Vaka, Dedeepya; Butte, Atul J.; Kay, Mark A.; Sage, Julien

doi:10.1016/j.celrep.2014.06.025

Cited by 32 publications

(42 citation statements)

References 42 publications

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“…We also found that expression of E2F target genes is positively associated with YAP function in vivo (Fig. S4D, S7D, E), consistent with prior work demonstrating cooperative interactions between YAP and E2F in the liver (Ehmer et al, 2014). Notably, we observed YAP-mediated modulation of HNF4A targets and E2F targets in vitro using primary HCC cultures, suggesting that the regulatory interactions may be direct (Fig.…”

Section: Discussionsupporting

confidence: 90%

YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression

et al. 2015

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SUMMARY Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. YAP functions as a rheostat maintaining metabolic specialization, differentiation and quiescence within the hepatocyte compartment. Increased or decreased YAP activity reprograms subsets of hepatocytes to different fates associated with deregulation of the HNF4A, CTNNB1, and E2F transcriptional programs controlling hepatocyte quiescence and differentiation. Importantly, treatment with siRNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model. Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of positional identity of hepatocytes, supports targeting YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype potentially responsive to this approach.

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Section: Discussionsupporting

confidence: 90%

YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression

et al. 2015

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“…We and others have shown that E2F and YAP/TEAD coordinately regulate a transcriptional program in cell cycle control in mammalian cells (23, 128, 129), a function that is conserved in Drosophila (130) (Figure 3A). …”

Section: Transcriptional Control Of Proliferationmentioning

confidence: 92%

“…In hepatocytes, unrestricted E2F activity in mice with hepatic inactivation of all three RB family members leads to cell cycle entry. However, inactivation and downregulation of YAP and TEAD1 counteracts the proliferative response in this model, is associated with reduced expression of E2F target genes and ultimately induction of complete cell cycle arrest (128). In pancreatic cancer, where activation of YAP can compensate for loss of oncogenic KRAS to maintain tumor cell proliferation independent of the KRAS signaling cascade, YAP/TEAD2 and E2F1 coordinately bind to several cell cycle associated target genes in YAP activated tumors (23).…”

Section: Transcriptional Control Of Proliferationmentioning

confidence: 99%

Control of Proliferation and Cancer Growth by the Hippo Signaling Pathway

Ehmer

Sage

2016

Molecular Cancer Research

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126

102

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The control of cell division is essential for normal development and the maintenance of cellular homeostasis. Abnormal cell proliferation is associated with multiple pathological states, including cancer. While the Hippo/YAP signaling pathway was initially thought to control organ size and growth, increasing evidence indicates that this pathway also plays a major role in the control of proliferation independent of organ size control. In particular, accumulating evidence indicates that the Hippo/YAP signaling pathway functionally interacts with multiple other cellular pathways and serves as a central node in the regulation of cell division, especially in cancer cells. Here recent observations are highlighted that connect Hippo/YAP signaling to transcription, the basic cell cycle machinery, and the control of cell division. Furthermore, the oncogenic and tumor suppressive attributes of YAP/TAZ are reviewed which emphasizes the relevance of the Hippo pathway in cancer.

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“…Drosophila eyes and wings have provided an advantageous system with which to study this process, as they undergo a relatively synchronized cell cycle exit during metamorphosis, have fewer paralogs and there are tools for precise conditional genetic manipulations. We used this system to examine cell cycle exit in terminally differentiating tissues and found that even in RB family member Rbf1 (Rbf -FlyBase)-deficient cells, Cyclin E/Cdk2 overexpression delays but cannot bypass cell cycle exit (Buttitta et al, 2007), suggesting that additional downstream mechanisms ensure the transition from proliferation to quiescence in vivo (Ehmer et al, 2014;Nicolay et al, 2010;Simon et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Protein phosphatase 2A promotes the transition to G0 during terminal differentiation in Drosophila

Sun

Buttitta

2015

Development

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Protein phosphatase type 2A complex (PP2A) has been known as a tumor suppressor for over two decades, but it remains unclear exactly how it suppresses tumor growth. Here, we provide data indicating a novel role for PP2A in promoting the transition to quiescence upon terminal differentiation in vivo. Using Drosophila eyes and wings as a model, we find that compromising PP2A activity during the final cell cycle prior to a developmentally controlled cell cycle exit leads to extra cell divisions and delays entry into quiescence. By systematically testing the regulatory subunits of Drosophila PP2A, we find that the B56 family member widerborst (wdb) is required for the role of PP2A in promoting the transition to quiescence. Cells in differentiating tissues with compromised PP2A retain high Cdk2 activity when they should be quiescent, and genetic epistasis tests demonstrate that ectopic Cyclin E/Cdk2 activity is responsible for the extra cell cycles caused by PP2A inhibition. The loss of wdb/PP2A function cooperates with aberrantly high Cyclin E protein levels, allowing cells to bypass a robust G0 late in development. This provides an example of how loss of PP2A can cooperate with oncogenic mutations in cancer. We propose that the PP2A complex plays a novel role in differentiating tissues to promote developmentally controlled quiescence through the regulation of Cyclin E/Cdk2 activity.

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Organ Size Control Is Dominant over Rb Family Inactivation to Restrict Proliferation In Vivo

Cited by 32 publications

References 42 publications

YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression

YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression

Control of Proliferation and Cancer Growth by the Hippo Signaling Pathway

Protein phosphatase 2A promotes the transition to G0 during terminal differentiation in Drosophila

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