The <i>SIL</i> Gene Is Essential for Mitotic Entry and Survival of Cancer Cells

Erez, Ayelet; Castiel, Asher; Trakhtenbrot, Luba; Perelman, Marina; Rosenthal, Esther; Goldstein, Itamar; Stettner, Noa; Harmelin, Alon; Eldar-Finkelman, Hagit; Campaner, Stefano; Kirsch, Ilan R.; Izraeli, Shai

doi:10.1158/0008-5472.can-07-0064

Cited by 39 publications

(51 citation statements)

References 16 publications

(20 reference statements)

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“…STIL is overexpressed in multiple cancers and its overexpression is associated with a metastatic phenotype and poor prognosis (Erez et al, 2004;Ramaswamy et al, 2003). In addition, knockdown of STIL in cancer cells delays entry into mitosis and induced apoptosis in several cancer cell lines (Erez et al, 2007). From these data, it might be speculated that overexpression of STIL in mammalian cells contributes to malignant transformation through the formation of supernumerary centrosomes, as observed for SAK in flies.…”

Section: Discussionmentioning

confidence: 90%

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STIL is required for centriole duplication in human cells

Vulprecht

David

Tibelius

et al. 2012

Journal of Cell Science

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172

184

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SummaryCentrioles are key structural elements of centrosomes and primary cilia. In mammals, only a few proteins including PLK4, CPAP (CENPJ), SAS6, CEP192, CEP152 and CEP135 have thus far been identified to be required for centriole duplication. STIL (SCL/TAL1 interrupting locus, also known as SIL) is a centrosomal protein that is essential for mouse and zebrafish embryonic development and mutated in primary microcephaly. Here, we show that STIL localizes to the pericentriolar material surrounding parental centrioles. Its overexpression results in excess centriole formation. siRNA-mediated depletion of STIL leads to loss of centrioles and abrogates PLK4-induced centriole overduplication. Additionally, we show that STIL is necessary for SAS6 recruitment to centrioles, suggesting that it is essential for daughter centriole formation, interacts with the centromere protein CPAP and rapidly shuttles between the cytoplasm and centrioles. Consistent with the requirement of centrioles for cilia formation, Stil -/-mouse embryonic fibroblasts lack primary cilia -a phenotype that can be reverted by restoration of STIL expression. These findings demonstrate that STIL is an essential component of the centriole replication machinery in mammalian cells.

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Section: Discussionmentioning

confidence: 90%

“…Alternatively, HeLa cells were transiently transfected with a vector encoding shRNA targeting STIL (pLKO.1, target sequence: 59-AAGACAACTGCTGTTGAAGAC-39) or control sequence (59-CAACAAGATGAAGAGCACCAA-39) (Erez et al, 2007).…”

Section: Rna Interferencementioning

confidence: 99%

STIL is required for centriole duplication in human cells

Vulprecht

David

Tibelius

et al. 2012

Journal of Cell Science

Self Cite

172

184

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“…Moreover, STIL expression was reported to be high in lung cancer (Erez et al, 2004) and most interestingly, mutations in STIL were recently shown to cause primary microcephaly (Kumar et al, 2009). Additional studies point to a possible role for STIL in cell proliferation, mitotic regulation and centrosome integrity (Izraeli et al, 1997;Campaner et al, 2005;Erez et al, 2007;Castiel et al, 2011), but the precise function of this protein remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Cell-cycle-regulated expression of STIL controls centriole number in human cells

Arquint

Sonnen

Stierhof

et al. 2012

Journal of Cell Science

171

219

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SummaryControl of centriole number is crucial for genome stability and ciliogenesis. Here, we characterize the role of human STIL, a protein that displays distant sequence similarity to the centriole duplication factors Ana2 in Drosophila and SAS-5 in Caenorhabditis elegans. Using RNA interference, we show that STIL is required for centriole duplication in human cells. Conversely, overexpression of STIL triggers the near-simultaneous formation of multiple daughter centrioles surrounding each mother, which is highly reminiscent of the phenotype produced by overexpression of the polo-like kinase PLK4 or the spindle assembly abnormal protein 6 homolog (SAS-6). We further show, by fluorescence and immunoelectron microscopy, that STIL is recruited to nascent daughter centrioles at the onset of centriole duplication and degraded, in an APC/C Cdc20-Cdh1 -dependent manner, upon passage through mitosis. We did not detect a stable complex between STIL and SAS-6, but the two proteins resemble each other with regard to both localization and cell cycle control of expression. Thus, STIL cooperates with SAS-6 and PLK4 in the control of centriole number and represents a key centriole duplication factor in human cells.

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“…Cytoplasmic protein SCL/TAL1 interrupting locus (SIL) is implicated in the mitotic activity and cellular proliferation of cancer cells (11)(12)(13). Sil null mouse embryos are lethal in the early stage of development with abnormal left-right specification (14), which are also found in sonic hedgehog (shh) null embryos (14)(15)(16), and double null embryos of sil and patched1, in which the intracellular Hedgehog (Hh) signaling should be constitutively activated, were phenotypically identical with sil null embryos (17).…”

Section: Introductionmentioning

confidence: 99%

SCL/TAL1 Interrupting Locus Derepresses GLI1 from the Negative Control of Suppressor-of-Fused in Pancreatic Cancer Cell

Kasai¹,

Inaguma²,

Yoneyama³

et al. 2008

Cancer Research

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As a physically binding protein of GLI1 transcription factor, Suppressor-of-Fused (SUFU) has been placed in the center of negative regulation of Hedgehog (Hh) signaling. SUFU tethers GLI1 in cytoplasm, and in some circumstances, it moves into the nucleus in association with GLI1, leading to the suppression of GLI1 target gene expression by recruiting a corepressor complex. The activated transcriptional function of GLI1 is important for cellular proliferation in a variety of human cancers. However, it has not been revealed how GLI1 is derepressed from SUFU-mediated suppression. Here, we show SCL/TAL1 interrupting locus (SIL) product, a cytoplasmic protein overexpressed in pancreatic ductal adenocarcinoma (PDA), is responsible for the derepression of GLI1. We found SIL associated with the carboxyl terminus of SUFU, one of two distinct GLI1-binding domains, and this association was responsible for cytoplasmic tethering of SUFU. Overexpressed SIL attenuated SUFU-mediated cytoplasmic tethering and target gene suppression of GLI1. Knockdown of SIL in PDA cells conversely induced the nuclear accumulation of SUFU in association with GLI1 and the transcriptional suppression of GLI1 target genes. Importantly, we also showed that oncogenic K-RAS, and not Sonic hedgehog, enhanced the SIL association with the amino-terminus of SUFU, the other GLI1-binding domain that led to further increase of nuclear translocation of GLI1. These results uncover the role of SIL in derepressing GLI1 from the negative control of SUFU, which is a crucial step for activating Hh signaling in cancer cells. [Cancer Res 2008;68(19):7723-9]

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The SIL Gene Is Essential for Mitotic Entry and Survival of Cancer Cells

Cited by 39 publications

References 16 publications

STIL is required for centriole duplication in human cells

STIL is required for centriole duplication in human cells

Cell-cycle-regulated expression of STIL controls centriole number in human cells

SCL/TAL1 Interrupting Locus Derepresses GLI1 from the Negative Control of Suppressor-of-Fused in Pancreatic Cancer Cell

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