The novel centrosomal associated protein CEP55 is present in the spindle midzone and the midbody

Martínez-Garay, Isabel; Rustom, Amin; Gerdes, Hans‐Hermann; Kutsche, Kerstin

doi:10.1016/j.ygeno.2005.11.006

Cited by 76 publications

(92 citation statements)

References 32 publications

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“…This behavior is well documented for CEP55, which migrates from the centrosome to the midbody upon phosphorylation by Cdk1 and Erk2 (18,33,34). Cell cycle-dependent centrosomal and midbody localization patterns have now also been reported for IST1 (22) and VPS4 (this study) and for the CHMP4-binding protein, TTC19, which was recently show to translocate together with its binding partner, FYVE-CENT, from centrosomes to midbodies (35).…”

Section: Discussionsupporting

confidence: 69%

Human ESCRT-III and VPS4 proteins are required for centrosome and spindle maintenance

Morita¹,

Colf²,

Karren³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

190

208

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The ESCRT pathway helps mediate the final abscission step of cytokinesis in mammals and archaea. In mammals, two early acting proteins of the ESCRT pathway, ALIX and TSG101, are recruited to the midbody through direct interactions with the phosphoprotein CEP55. CEP55 resides at the centrosome through most of the cell cycle but then migrates to the midbody at the start of cytokinesis, suggesting that the ESCRT pathway may also have centrosomal links. Here, we have systematically analyzed the requirements for late-acting mammalian ESCRT-III and VPS4 proteins at different stages of mitosis and cell division. We found that depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission. Remarkably, depletion of individual ESCRT-III and VPS4 proteins also altered centrosome and spindle pole numbers, producing multipolar spindles (most ESCRT-III/VPS4 proteins) or monopolar spindles (CHMP2A or CHMP5) and causing defects in chromosome segregation and nuclear morphology. VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis, implying that these proteins function directly at both sites. We conclude that ESCRT-III/VPS4 proteins function at centrosomes to help regulate their maintenance or proliferation and then at midbodies during abscission, thereby helping ensure the ordered progression through the different stages of cell division.T he ESCRT pathway functions across eukaryotes and many archaeal species, where it helps mediate (i) vesicle formation at multivesicular bodies (MVB) (1), (ii) enveloped virus budding (2), and (iii) the abscission stage of cytokinesis (3-7). These seemingly disparate biological processes all involve the resolution of thin, cytoplasm-filled membrane tubules, implying that ESCRT machinery can be recruited to different biological membranes to mediate topologically similar membrane fission events. Most ESCRT pathway proteins function as subunits of five multiprotein complexes, termed the ESCRT-0, -I, -II, -III, and VPS4 complexes. Other ESCRT factors, such as ALIX, function as discrete proteins. Classic studies in yeast have established that the ESCRT components are recruited sequentially to endosomal membranes where they assemble into higher order complexes that mediate protein sorting, membrane remodeling, and fission (8). Initially, early-acting factors such as ESCRT-I, ESCRT-II, and ALIX interact with upstream recruiting factors, concentrate protein cargoes, and help deform membranes (9). These early-acting factors recruit subunits of the ESCRT-III complex, which form filaments within the necks of membrane tubules and mediate membrane fission (10-16). ESCRT-III assemblies, in turn, recruit VPS4 ATPases, which use the energy of ATP hydrolysis to disassemble the ESCRT complexes (10-14, 17).ESCRT-III and VPS4 homologs mediate abscission in hyperthermophilic crenarchaeal species that diverged from eukaryotes several billion years ago, suggesting that cell division may have been the primordial function of the E...

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Section: Discussionsupporting

confidence: 69%

Human ESCRT-III and VPS4 proteins are required for centrosome and spindle maintenance

Morita¹,

Colf²,

Karren³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

190

208

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“…[12][13][14] Consistent with CEP55 being a direct transcriptional target of FOXM1, 7 both CEP55 12 and FOXM1 31 share organ-specific expression in the testis and thymus of normal adult humans. CEP55 is upregulated in hepatocellular carcinoma and its overexpression induces anchorage-independent growth, enhanced cell growth at low serum levels and induction of tumourigenesis in nude mice.…”

Section: Discussionmentioning

confidence: 89%

“…However, it has been shown that the frequency of HNSCCs that have integrated HPV and express high levels E7 is only in the region of 4-16%. 10,11 We have recently shown that aberrant upregulation of FOXM1 serves as a first oncogenic hit by destabilising the genome and subsequent activation of downstream targets which regulates cytokinesis (CEP55, centrosomal protein 55kDa) [12][13][14] and epigenetic/stem-cell factor re-programming (HELLS, helicase lymphoid specific) [15][16][17][18] leading to malignant transformation (anchorage-independent growth) of a premalignant oral keratinocyte line (SVpgC2a). 7 However, the protein expression profiles of CEP55 and HELLS during HNSCC progression have not been described.…”

Section: Introductionmentioning

confidence: 99%

Downstream targets of FOXM1: CEP55 and HELLS are cancer progression markers of head and neck squamous cell carcinoma

et al. 2010

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AbbreviationsHNSCC, head and neck squamous cell carcinoma; FOXM1, forkhead box M1; CEP55, centrosomal protein 55; HELLS, lymphoid specific helicase; qPCR, absolute real time reverse transcription quantitative polymerase chain reaction; NHOK, primary normal human oral keratinocytes; LnMet, lymph node metastasis; FFPE, formalin-fixed paraffin embedded. ABSTRACTWe recently showed that upregulation of a key oncogene FOXM1 precedes head and neck squamous cell carcinoma (HNSCC) malignancy. Furthermore, we also identified a centrosomal protein CEP55 and a DNA helicase/putative stem cell marker HELLS, which are both downstream targets of FOXM1.In this study, we have investigated the expression profiles of CEP55 and HELLS using immunohistochemistry and quantified by digital densitometry in a tissue panel (20 samples) consisting of normal oral mucosa, dysplasias, HNSCC and lymph node metastasis (LnMet) samples.Furthermore, we corroborated our findings using absolute real-time PCR (qPCR) on a panel of 12 primary normal human oral keratinocytes, 5 dysplasia and 10 HNSCC cell lines. Finally, we validated our study using bioinformatics microarray analysis on an independent HNSCC patient cohort (4 normal and 16 tumours). In normal oral mucosa, CEP55 protein was detected at very low level within the upper differentiated layers. In contrast, CEP55 was highly expressed in oral dysplasia whereas only moderate expression was detected in HNSCC and LnMet. Low level of HELLS expression was detected in the basal cell layer of the normal oral mucosa, moderate level was seen in dysplasia and high levels in both HNSCC and LnMet. These expression patterns were consistent with both qPCR data from the cell line panel and microarray data analysis of TNM-stage defined HNSCC samples confirming the progressive expression pattern of CEP55 and HELLS. To our knowledge, this is the first pilot study demonstrating that both CEP55 and HELLS mRNA and protein expression positively correlate with pre-malignancy and HNSCC progression. This study provides strong evidence that CEP55 and HELLS may be used in conjunction with FOXM1 as a biomarker set for early cancer detection and indicators of malignant conversion and progression.

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“…Cep55 encodes a centrosomal associated protein involved in centrosome duplication, cell-cycle progression, and in the regulation of cytokinesis (41). Kif2c encodes a kinesin-like protein which has a role in bipolar spindle assembly (42).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Gene Expression and Cell-Cycle Signaling Pathways by the EGFR Inhibitor Gefitinib (Iressa) in Rat Urinary Bladder Cancer

Lü

Liu

Bergh

et al. 2012

Cancer Prevention Research

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The epidermal growth factor receptor inhibitor Iressa has shown strong preventive efficacy in the N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) model of bladder cancer in the rat. To explore its antitumor mechanism, we implemented a systems biology approach to characterize gene expression and signaling pathways in rat urinary bladder cancers treated with Iressa. Eleven bladder tumors from control rats, seven tumors from rats treated with Iressa, and seven normal bladder epithelia were profiled by the Affymetrix Rat Exon 1.0 ST Arrays. We identified 713 downregulated and 641 upregulated genes in comparing bladder tumors versus normal bladder epithelia. In addition, 178 genes were downregulated and 96 genes were upregulated when comparing control tumors versus Iressa-treated tumors. Two coexpression modules that were significantly correlated with tumor status and treatment status were identified [r ¼ 0.70, P ¼ 2.80 Â 10 À15 (bladder tumor vs. normal bladder epithelium) and r ¼ 0.63, P ¼ 2.00 Â 10 À42 (Iressa-treated tumor vs. control tumor), respectively]. Both tumor module and treatment module were enriched for genes involved in cell-cycle processes. Twenty-four and twenty-one highly connected hub genes likely to be key drivers in cell cycle were identified in the tumor module and treatment module, respectively. Analysis of microRNA genes on the array chips showed that tumor module and treatment module were significantly associated with expression levels of let-7c (r ¼ 0.54, P ¼ 3.70 Â 10 À8 and r ¼ 0.73, P ¼ 1.50 Â 10 À65 , respectively). These results suggest that let-7c downregulation and its regulated cell-cycle pathway may play an integral role in governing bladder tumor suppression or collaborative oncogenesis and that Iressa exhibits its preventive efficacy on bladder tumorigenesis by upregulating let-7 and inhibiting the cell cycle. Cell culture study confirmed that the increased expression of let-7c decreases Iressa-treated bladder tumor cell growth. The identified hub genes may also serve as pharmacodynamic or efficacy biomarkers in clinical trials of chemoprevention in human bladder cancer. Cancer Prev Res; 5(2); 248-59. Ó2011 AACR.

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The novel centrosomal associated protein CEP55 is present in the spindle midzone and the midbody

Cited by 76 publications

References 32 publications

Human ESCRT-III and VPS4 proteins are required for centrosome and spindle maintenance

Human ESCRT-III and VPS4 proteins are required for centrosome and spindle maintenance

Downstream targets of FOXM1: CEP55 and HELLS are cancer progression markers of head and neck squamous cell carcinoma

Modulation of Gene Expression and Cell-Cycle Signaling Pathways by the EGFR Inhibitor Gefitinib (Iressa) in Rat Urinary Bladder Cancer

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