Cell cycle regulation of the human Six1 homeoprotein is mediated by APCCdh1

Christensen, Kimberly; Brennan, J D G; Aldridge, Carrie S.; Ford, Heide L.

doi:10.1038/sj.onc.1210122

Cited by 35 publications

(28 citation statements)

References 37 publications

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“…The present study examined the effect of SIX1 on cell cycle progression and found that SIX1 overexpression upregulated, while SIX1 depletion downregulated, cyclin D1 and cyclin E expression; a finding that was in accordance with previous reports (15,32,33). The present study further investigated the molecular pathways involved in SIX1-induced cancer progression.…”

Section: Discussionsupporting

confidence: 78%

SIX1 is overexpressed in endometrial carcinoma and promotes the malignant behavior of cancer cells through ERK and AKT signaling

Xin

Yang

2016

Oncology Letters

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Abstract. The sineoculis homeobox homolog 1 (SIX1) protein has been found to be important for cancer progression. However, its biological role in human endometrial carcinomas remains unexplored. The potential mechanism of SIX1-induced cancer progression remains unclear. In the present study, SIX1 protein expression was examined in 84 cases of endometrial carcinoma tissues using immunohistochemisty, and SIX1 was found to be overexpressed in 51.1% (43/84) of cervical cancer cells. Small interfering RNA (siRNA) knockdown of SIX1 was also performed in Ishikawa cells with high endogenous SIX1 expression, and SIX1 was overexpressed in the HEC1B cell line with low endogenous expression. SIX1 overexpression promoted cell growth rate and colony formation ability, whereas SIX1 depletion inhibited cell growth and colony formation. Further analysis showed that SIX1 knockdown downregulated, and SIX1 overexpression upregulated, cyclin D1, cyclin E, phosphorylated (p-)extracellular signal-regulated kinase (ERK), and p-protein kinase B (AKT) expression. The ERK inhibitor, U0126, and AKT inhibitor treatments blocked the effect of SIX1 on proliferation. In conclusion, the present study found that SIX1 overexpression promotes cancer cell growth in endometrial carcinoma, possibly through ERK-and AKT-mediated pathways.

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Section: Discussionsupporting

confidence: 78%

SIX1 is overexpressed in endometrial carcinoma and promotes the malignant behavior of cancer cells through ERK and AKT signaling

Xin

Yang

2016

Oncology Letters

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“…This is not unexpected, as a similar observation was previously described for several cell cycle regulators (34,35). It is noteworthy that SIX1, the DNA-binding protein and cofactor of EYA1, is also degraded in a pathway involving APC/C-Cdh1 in a cell cycle-dependent manner, and its degradation is also independent of known APC degradation motifs (35). Previous studies have suggested that substrates lacking canonical D-boxes contain a three-dimensional interaction surface similar to a D-box but with a different primary amino acid sequence (36).…”

Section: Discussionsupporting

confidence: 62%

“…However, these known motifs are not critical for targeting by Cdh1, as mutating either motif had no effect on its interaction with Cdh1 and degradation by APC/C-Cdh1, suggesting that novel APC/C-Cdh1-targeting motifs exist. This is not unexpected, as a similar observation was previously described for several cell cycle regulators (34,35). It is noteworthy that SIX1, the DNA-binding protein and cofactor of EYA1, is also degraded in a pathway involving APC/C-Cdh1 in a cell cycle-dependent manner, and its degradation is also independent of known APC degradation motifs (35).…”

Section: Discussionsupporting

confidence: 52%

The Phosphatase-Transcription Activator EYA1 Is Targeted by Anaphase-Promoting Complex/Cdh1 for Degradation at M-to-G₁ Transition

Sun

Karoulia

Wong

et al. 2013

Molecular and Cellular Biology

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The phosphatase and transactivator EYA family proteins are overexpressed in many cancer cell lines and are abundantly distributed in undifferentiated cells during development. Loss-of-function studies have shown that EYA1 is required for cell proliferation and survival during mammalian organogenesis. However, how EYA1 is regulated during development is unknown. Here, we report that EYA1 is regulated throughout the cell cycle via ubiquitin-mediated proteolysis. The level of EYA1 protein fluctuates in the cell cycle, peaking during mitosis and dropping drastically as cells exit into G 1 . We found that EYA1 is efficiently degraded during mitotic exit in a Cdh1-dependent manner and that these two proteins physically interact. Overexpression of Cdh1 reduces the protein levels of ectopically expressed or endogenous EYA1, whereas depletion of Cdh1 by RNA interference stabilizes the EYA1 protein. Together, our results indicate that anaphase-promoting complex/cyclosome (APC/C)-Cdh1 specifically targets EYA1 for degradation during M-to-G 1 transition, failure of which may compromise cell proliferation and survival. The eyes absent (EYA) family proteins is composed of four members (EYA1 to EYA4) defined by a conserved C-terminal Eya domain, which interacts with other proteins and has an intrinsic phosphatase activity (1-3). The EYA proteins possess a transactivation domain in their N-terminal regions (4) and act as transcriptional coactivators by interacting with DNA-binding proteins, such as the homeodomain SIX family proteins, to transactivate genes that are essential for normal development during mammalian organogenesis (4-7). Mutations in the human EYA1 cause branchio-oto-renal (BOR) and branchio-oto (BO) syndromes, which are characterized by branchial arch abnormalities and hearing loss with or without kidney defects (8-11). Deletion of either gene in mice results in the absence of the inner ear, kidney, and thymus as well as reduction of other tissues (10,12,13).During mouse embryonic development, Eya1 is expressed in early progenitor cells in several organ primordia and regulates cell proliferation and survival, as its inactivation in mice leads to reduced proliferation and increased apoptosis in several organ primordia (10,(12)(13)(14)(15). In Drosophila, overexpression of EYA results in overproliferation, while their loss leads to tissue reduction (7,16). Recent studies have found that the levels of EYA proteins are elevated in several cancer cells (17)(18)(19)(20). While a recent study reported that EYA may promote DNA repair by dephosphorylating histone ␥H2AX (21), how EYA acts to regulate cell proliferation and its precise mode of action in cell cycle regulation remain largely unknown. Furthermore, although the biochemical functions of EYA proteins and the spatiotemporal expression pattern of their mRNAs during mouse development have been well studied, it is currently unknown how the levels of EYA proteins are regulated during development.Most eukaryotic cell cycle regulators require targeted degradation to ma...

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“…Western blotting was performed on nuclear extracts as previously described (28). Immunecomplex kinase assays, RNA isolation, and quantitative reverse transcription-PCR were performed as previously described (15).…”

Section: Methodsmentioning

confidence: 99%

Six1 Overexpression in Mammary Cells Induces Genomic Instability and Is Sufficient for Malignant Transformation

Coletta

Christensen²,

Micalizzi³

et al. 2008

Cancer Research

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Homeoproteins are transcription factors that act as master regulators of development and are frequently dysregulated in cancers. During embryogenesis, the Six1 homeoprotein is essential for the expansion of precursor cell populations that give rise to muscle and kidney, among other organs. Six1 overexpression is observed in numerous cancers, resulting in increased proliferation, survival, and metastasis. Here, we investigate whether Six1 can play a causal role in mammary tumor initiation. We show that Six1 overexpression in MCF12A mammary epithelial cells promotes multiple properties associated with malignant transformation, including increased proliferation, genomic instability, and anchorageindependent growth. We further show that this transformation is dependent on up-regulation of its transcriptional target, cyclin A1, which is normally expressed in the embryonic mammary gland but dramatically reduced in the adult gland. Six1-transformed MCF12A cells are tumorigenic in nude mice, forming aggressive tumors that are locally invasive and exhibit peritumoral lymphovascular invasion. In human breast carcinomas, expression of Six1 and cyclin A1 mRNA correlate strongly with each other (P < 0.0001), and expression of Six1 and cyclin A1 each correlate with Ki67, a marker of proliferation (P < 0.0001 and P = 0.014, respectively). Together, our data indicate that Six1 overexpression is sufficient for malignant transformation of immortalized, nontumorigenic mammary epithelial cells, and suggest that the mechanism of this transformation involves inappropriate reexpression of cyclin A1 in the adult mammary gland. [Cancer Res 2008;68(7):2204-13]

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Cell cycle regulation of the human Six1 homeoprotein is mediated by APCCdh1

Cited by 35 publications

References 37 publications

SIX1 is overexpressed in endometrial carcinoma and promotes the malignant behavior of cancer cells through ERK and AKT signaling

SIX1 is overexpressed in endometrial carcinoma and promotes the malignant behavior of cancer cells through ERK and AKT signaling

The Phosphatase-Transcription Activator EYA1 Is Targeted by Anaphase-Promoting Complex/Cdh1 for Degradation at M-to-G₁ Transition

Six1 Overexpression in Mammary Cells Induces Genomic Instability and Is Sufficient for Malignant Transformation

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Cell cycle regulation of the human Six1 homeoprotein is mediated by APCCdh1

Cited by 35 publications

References 37 publications

SIX1 is overexpressed in endometrial carcinoma and promotes the malignant behavior of cancer cells through ERK and AKT signaling

SIX1 is overexpressed in endometrial carcinoma and promotes the malignant behavior of cancer cells through ERK and AKT signaling

The Phosphatase-Transcription Activator EYA1 Is Targeted by Anaphase-Promoting Complex/Cdh1 for Degradation at M-to-G1 Transition

Six1 Overexpression in Mammary Cells Induces Genomic Instability and Is Sufficient for Malignant Transformation

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The Phosphatase-Transcription Activator EYA1 Is Targeted by Anaphase-Promoting Complex/Cdh1 for Degradation at M-to-G₁ Transition