Hippo Pathway and Apoptosis

Hamilton, Garth; O’Neill, Eric

doi:10.1007/978-1-4614-6220-0_7

Cited by 4 publications

(2 citation statements)

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“…In summary, LATS2 kinase promotes cell death downstream of DDK inhibition, but this function may be independent of its canonical role in the Hippo signaling pathway. Interestingly, Hippo signaling has previously been shown to induce apoptosis under conditions of stress, and LATS2 can promote apoptosis through p53 stabilization and in polyploid cells [53] . Since LATS2 kinase promotes apoptosis in both breast cancer (HCC1954) and cervical cancer (HeLa) cell lines, which are both p53-deficient cells, the mechanism of apoptotic induction is likely mediated through a target different from p53.…”

Section: Resultsmentioning

confidence: 99%

DDK Promotes Tumor Chemoresistance and Survival via Multiple Pathways

Sasi

Bhutkar

Lanning³

et al. 2017

Neoplasia

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DBF4-dependent kinase (DDK) is a two-subunit kinase required for initiating DNA replication at individual origins and is composed of CDC7 kinase and its regulatory subunit DBF4. Both subunits are highly expressed in many diverse tumor cell lines and primary tumors, and this is correlated with poor prognosis. Inhibiting DDK causes apoptosis of tumor cells, but not normal cells, through a largely unknown mechanism. Firstly, to understand why DDK is often overexpressed in tumors, we identified gene expression signatures that correlate with DDK high- and DDK low-expressing lung adenocarcinomas. We found that increased DDK expression is highly correlated with inactivation of RB1-E2F and p53 tumor suppressor pathways. Both CDC7 and DBF4 promoters bind E2F, suggesting that increased E2F activity in RB1 mutant cancers promotes increased DDK expression. Surprisingly, increased DDK expression levels are also correlated with both increased chemoresistance and genome-wide mutation frequencies. Our data further suggest that high DDK levels directly promote elevated mutation frequencies. Secondly, we performed an RNAi screen to investigate how DDK inhibition causes apoptosis of tumor cells. We identified 23 kinases and phosphatases required for apoptosis when DDK is inhibited. These hits include checkpoint genes, G2/M cell cycle regulators, and known tumor suppressors leading to the hypothesis that inhibiting mitotic progression can protect against DDKi-induced apoptosis. Characterization of one novel hit, the LATS2 tumor suppressor, suggests that it promotes apoptosis independently of the upstream MST1/2 kinases in the Hippo signaling pathway.

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Section: Resultsmentioning

confidence: 99%

DDK Promotes Tumor Chemoresistance and Survival via Multiple Pathways

Sasi

Bhutkar

Lanning³

et al. 2017

Neoplasia

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“…It would be desirable to describe the distribution of Yki in nuclei versus cytoplasm in other life stages of C. hemisphaerica (embryonic development, planula larva, polyp colony) using the anti-CheYki antibody designed in this study. In addition to monitoring areas of cell division with EdU as in the present work, it would also be of interest to look for a link between Yki localisation and apoptosis, since in bilaterians nuclear Yki not only promotes cell division but also inhibits apoptosis [ 66 ]. Drugs affecting the Hpo pathway would be extremely useful to gain a better understanding of its functions (notably with respect to organ size), especially since tools to inactivate or upregulate specific genes in P. pileus or in the C. hemisphaerica adults (polyps and medusae) are not yet established.…”

Section: Discussionmentioning

confidence: 99%

Comparative study of Hippo pathway genes in cellular conveyor belts of a ctenophore and a cnidarian

Coste

Jager

Chambon

et al. 2016

EvoDevo

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BackgroundThe Hippo pathway regulates growth rate and organ size in fly and mouse, notably through control of cell proliferation. Molecular interactions at the heart of this pathway are known to have originated in the unicellular ancestry of metazoans. They notably involve a cascade of phosphorylations triggered by the kinase Hippo, with subsequent nuclear to cytoplasmic shift of Yorkie localisation, preventing its binding to the transcription factor Scalloped, thereby silencing proliferation genes. There are few comparative expression data of Hippo pathway genes in non-model animal species and notably none in non-bilaterian phyla.ResultsAll core Hippo pathway genes could be retrieved from the ctenophore Pleurobrachia pileus and the hydrozoan cnidarian Clytia hemisphaerica, with the important exception of Yorkie in ctenophore. Expression study of the Hippo, Salvador and Scalloped genes in tentacle “cellular conveyor belts” of these two organisms revealed striking differences. In P. pileus, their transcripts were detected in areas where undifferentiated progenitors intensely proliferate and where expression of cyclins B and D was also seen. In C. hemisphaerica, these three genes and Yorkie are expressed not only in the proliferating but also in the differentiation zone of the tentacle bulb and in mature tentacle cells. However, using an antibody designed against the C. hemiphaerica Yorkie protein, we show in two distinct cell lineages of the medusa that Yorkie localisation is predominantly nuclear in areas of active cell proliferation and mainly cytoplasmic elsewhere.ConclusionsThis is the first evidence of nucleocytoplasmic Yorkie shift in association with the arrest of cell proliferation in a cnidarian, strongly evoking the cell division-promoting role of this protein and its inhibition by the activated Hippo pathway in bilaterian models. Our results furthermore highlight important differences in terms of deployment and regulation of Hippo pathway genes between cnidarians and ctenophores.Electronic supplementary materialThe online version of this article (doi:10.1186/s13227-016-0041-y) contains supplementary material, which is available to authorized users.

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Ras and the Hippo Pathway in Cancer

O’Neill

2017

Conquering RAS

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Hippo Pathway and Apoptosis

Cited by 4 publications

References 167 publications

DDK Promotes Tumor Chemoresistance and Survival via Multiple Pathways

DDK Promotes Tumor Chemoresistance and Survival via Multiple Pathways

Comparative study of Hippo pathway genes in cellular conveyor belts of a ctenophore and a cnidarian

Ras and the Hippo Pathway in Cancer

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