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1.
Trends Genet ; 39(12): 954-967, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37714734

RESUMO

The overwhelming majority of proliferating somatic human cells are diploid, and this genomic state is typically maintained across successive cell divisions. However, failures in cell division can induce a whole-genome doubling (WGD) event, in which diploid cells transition to a tetraploid state. While some WGDs are developmentally programmed to produce nonproliferative tetraploid cells with specific cellular functions, unscheduled WGDs can be catastrophic: erroneously arising tetraploid cells are ill-equipped to cope with their doubled cellular and chromosomal content and quickly become genomically unstable and tumorigenic. Deciphering the genetics that underlie the genesis, physiology, and evolution of whole-genome doubled (WGD+) cells may therefore reveal therapeutic avenues to selectively eliminate pathological WGD+ cells.


Assuntos
Neoplasias , Tetraploidia , Humanos , Neoplasias/genética , Divisão Celular , Genoma/genética , Fenômenos Fisiológicos Celulares
2.
Cells ; 12(7)2023 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-37048053

RESUMO

Hyperactive sphingosine 1-phosphate (S1P) signaling is associated with a poor prognosis of triple-negative breast cancer (TNBC). Despite recent evidence that links the S1P receptor 1 (S1P1) to TNBC cell survival, its role in TNBC invasion and the underlying mechanisms remain elusive. Combining analyses of human TNBC cells with zebrafish xenografts, we found that phosphorylation of S1P receptor 1 (S1P1) at threonine 236 (T236) is critical for TNBC dissemination. Compared to luminal breast cancer cells, TNBC cells exhibit a significant increase of phospho-S1P1 T236 but not the total S1P1 levels. Misexpression of phosphorylation-defective S1P1 T236A (alanine) decreases TNBC cell migration in vitro and disease invasion in zebrafish xenografts. Pharmacologic disruption of S1P1 T236 phosphorylation, using either a pan-AKT inhibitor (MK2206) or an S1P1 functional antagonist (FTY720, an FDA-approved drug for treating multiple sclerosis), suppresses TNBC cell migration in vitro and tumor invasion in vivo. Finally, we show that human TNBC cells with AKT activation and elevated phospho-S1P1 T236 are sensitive to FTY720-induced cytotoxic effects. These findings indicate that the AKT-enhanced phosphorylation of S1P1 T236 mediates much of the TNBC invasiveness, providing a potential biomarker to select TNBC patients for the clinical application of FTY720.


Assuntos
Cloridrato de Fingolimode , Receptores de Esfingosina-1-Fosfato , Neoplasias de Mama Triplo Negativas , Animais , Humanos , Cloridrato de Fingolimode/farmacologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Treonina , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Peixe-Zebra/metabolismo
4.
Nature ; 590(7846): 492-497, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33505027

RESUMO

Whole-genome doubling (WGD) is common in human cancers, occurring early in tumorigenesis and generating genetically unstable tetraploid cells that fuel tumour development1,2. Cells that undergo WGD (WGD+ cells) must adapt to accommodate their abnormal tetraploid state; however, the nature of these adaptations, and whether they confer vulnerabilities that can be exploited therapeutically, is unclear. Here, using sequencing data from roughly 10,000 primary human cancer samples and essentiality data from approximately 600 cancer cell lines, we show that WGD gives rise to common genetic traits that are accompanied by unique vulnerabilities. We reveal that WGD+ cells are more dependent than WGD- cells on signalling from the spindle-assembly checkpoint, DNA-replication factors and proteasome function. We also identify KIF18A, which encodes a mitotic kinesin protein, as being specifically required for the viability of WGD+ cells. Although KIF18A is largely dispensable for accurate chromosome segregation during mitosis in WGD- cells, its loss induces notable mitotic errors in WGD+ cells, ultimately impairing cell viability. Collectively, our results suggest new strategies for specifically targeting WGD+ cancer cells while sparing the normal, non-transformed WGD- cells that comprise human tissue.


Assuntos
Genoma Humano/genética , Mitose/efeitos dos fármacos , Neoplasias/genética , Neoplasias/patologia , Tetraploidia , Cariótipo Anormal/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Genes Letais/genética , Humanos , Cinesinas/deficiência , Cinesinas/genética , Cinesinas/metabolismo , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Masculino , Mitose/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Reprodutibilidade dos Testes , Fuso Acromático/efeitos dos fármacos
5.
Nat Cell Biol ; 22(2): 246-256, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32015438

RESUMO

The Hippo and mammalian target of rapamycin complex 1 (mTORC1) pathways are the two predominant growth-control pathways that dictate proper organ development. We therefore explored potential crosstalk between these two functionally relevant pathways to coordinate their growth-control functions. We found that the LATS1 and LATS2 kinases, the core components of the Hippo pathway, phosphorylate S606 of Raptor, an essential component of mTORC1, to attenuate mTORC1 activation by impairing the interaction of Raptor with Rheb. The phosphomimetic Raptor-S606D knock-in mutant led to a reduction in cell size and proliferation. Compared with Raptor+/+ mice, RaptorD/D knock-in mice exhibited smaller livers and hearts, and a significant inhibition of elevation in mTORC1 signalling induced by Nf2 or Lats1 and Lats2 loss. Thus, our study reveals a direct link between the Hippo and mTORC1 pathways to fine-tune organ growth.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Proteínas Serina-Treonina Quinases/genética , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , Proteína Regulatória Associada a mTOR/genética , Proteínas Supressoras de Tumor/genética , Animais , Sistemas CRISPR-Cas , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Edição de Genes , Células HCT116 , Células HEK293 , Células HeLa , Xenoenxertos , Via de Sinalização Hippo , Humanos , Fígado/anormalidades , Fígado/metabolismo , Células MCF-7 , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Nus , Camundongos Transgênicos , Miocárdio/metabolismo , Miocárdio/patologia , Neurofibromina 2/deficiência , Neurofibromina 2/genética , Tamanho do Órgão , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Enriquecida em Homólogo de Ras do Encéfalo/metabolismo , Proteína Regulatória Associada a mTOR/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/deficiência
6.
Nat Commun ; 10(1): 1547, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30948712

RESUMO

The Hippo pathway maintains tissue homeostasis by negatively regulating the oncogenic transcriptional co-activators YAP and TAZ. Though functional inactivation of the Hippo pathway is common in tumors, mutations in core pathway components are rare. Thus, understanding how tumor cells inactivate Hippo signaling remains a key unresolved question. Here, we identify the kinase STK25 as an activator of Hippo signaling. We demonstrate that loss of STK25 promotes YAP/TAZ activation and enhanced cellular proliferation, even under normally growth-suppressive conditions both in vitro and in vivo. Notably, STK25 activates LATS by promoting LATS activation loop phosphorylation independent of a preceding phosphorylation event at the hydrophobic motif, which represents a form of Hippo activation distinct from other kinase activators of LATS. STK25 is significantly focally deleted across a wide spectrum of human cancers, suggesting STK25 loss may represent a common mechanism by which tumor cells functionally impair the Hippo tumor suppressor pathway.


Assuntos
Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Linhagem Celular , Proliferação de Células , Genes Supressores de Tumor , Via de Sinalização Hippo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais
7.
Methods Mol Biol ; 1893: 203-214, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30565136

RESUMO

The advent of CRISPR has revolutionized genomic engineering, and harnessing its power to regulate levels of the transcriptional co-activators YAP and TAZ represents an exciting new opportunity in the field of Hippo signaling. Initially repurposed from the microbial immune system to perform highly specific gene knockouts, CRISPR technology has now been expanded to modulate the transcriptional activity of any gene of interest in mammalian systems. Here, we describe strategies to employ CRISPR to genetically knock out the genes encoding for YAP (YAP1) or TAZ (WWTR1) in mammalian cell lines, as well as briefly outline an approach for utilizing CRISPR to transcriptionally modulate YAP/TAZ levels.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Aciltransferases , Proteínas de Ciclo Celular , Edição de Genes , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Vetores Genéticos , Via de Sinalização Hippo , Humanos , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , RNA Guia de Cinetoplastídeos , Transdução de Sinais , Fatores de Transcrição/metabolismo
8.
Mol Biol Cell ; 29(13): 1682-1692, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29791254

RESUMO

Tetraploid cells, which are most commonly generated by errors in cell division, are genomically unstable and have been shown to promote tumorigenesis. Recent genomic studies have estimated that ∼40% of all solid tumors have undergone a genome-doubling event during their evolution, suggesting a significant role for tetraploidy in driving the development of human cancers. To safeguard against the deleterious effects of tetraploidy, nontransformed cells that fail mitosis and become tetraploid activate both the Hippo and p53 tumor suppressor pathways to restrain further proliferation. Tetraploid cells must therefore overcome these antiproliferative barriers to ultimately drive tumor development. However, the genetic routes through which spontaneously arising tetraploid cells adapt to regain proliferative capacity remain poorly characterized. Here, we conducted a comprehensive gain-of-function genome-wide screen to identify microRNAs (miRNAs) that are sufficient to promote the proliferation of tetraploid cells. Our screen identified 23 miRNAs whose overexpression significantly promotes tetraploid proliferation. The vast majority of these miRNAs facilitate tetraploid growth by enhancing mitogenic signaling pathways (e.g., miR-191-3p); however, we also identified several miRNAs that impair the p53/p21 pathway (e.g., miR-523-3p), and a single miRNA (miR-24-3p) that potently inactivates the Hippo pathway via down-regulation of the tumor suppressor gene NF2. Collectively, our data reveal several avenues through which tetraploid cells may regain the proliferative capacity necessary to drive tumorigenesis.


Assuntos
Testes Genéticos , MicroRNAs/genética , Tetraploidia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Regulação para Baixo/genética , Humanos , MicroRNAs/metabolismo , Mitógenos/metabolismo , Neurofibromina 2/metabolismo , Fosfoproteínas/metabolismo , Transdução de Sinais , Fatores de Transcrição , Proteína Supressora de Tumor p53/metabolismo , Proteínas de Sinalização YAP
9.
Mol Biol Cell ; 27(21): 3210-3213, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27799497

RESUMO

The nuclear envelope, composed of two lipid bilayers and numerous accessory proteins, has evolved to house the genetic material of all eukaryotic cells. In so doing, the nuclear envelope provides a physical barrier between chromosomes and the cytoplasm. Once believed to be highly stable, recent studies demonstrate that the nuclear envelope is prone to rupture. These rupture events expose chromosomal DNA to the cytoplasmic environment and have the capacity to promote DNA damage. Thus nuclear rupture may be an unappreciated mechanism of mutagenesis.


Assuntos
Membrana Nuclear/metabolismo , Membrana Nuclear/fisiologia , Núcleo Celular/metabolismo , Núcleo Celular/fisiologia , Cromossomos/metabolismo , Citoplasma/metabolismo , Dano ao DNA/fisiologia , Células Eucarióticas/metabolismo , Instabilidade Genômica/genética , Neoplasias/genética , Proteínas Nucleares/metabolismo
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