Von Hippel-Lindau gene product directs cytokinesis: a new tumor suppressor function

Sinha, Sutapa; Mondal, Gourish; Hwang, Eun Ju; Han, Da Woon; Dutta, Shamit K.; Iyer, Seethalakshmi; Karumanchi, S. Ananth; Kim, Keun Il; Couch, Fergus J.; Mukhopadhyay, Debabrata

doi:10.1242/jcs.087122

Cited by 12 publications

(8 citation statements)

References 46 publications

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“…Remarkably, several cytokinesis genes/proteins have also been found to play roles in cancer pathogenesis [reviewed in Normand and King, 2010;Lacroix and Maddox, 2012]. Cytokinesis proteins are frequently upregulated in cancer cells or are encoded by genes that are deleted or amplified in human cancers [Roversi et al, 2006;Lind et al, 2011;Sinha et al, 2011]. Thus, clarification of the molecular pathways involved in cytokinesis may also aid cancer diagnosis and the design of therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

What Drosophila spermatocytes tell us about the mechanisms underlying cytokinesis

Giansanti

Fuller

2012

Cytoskeleton

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Cytokinesis separates the genomic material and organelles of a dividing cell equitably into two physically distinct daughter cells at the end of cell division. This highly choreographed process involves coordinated reorganization and regulated action of the actin and microtubule cytoskeletal systems, an assortment of motor proteins, and membrane trafficking components. Due to their large size, the ease with which exquisite cytological analysis may be performed on them, and the availability of numerous mutants and other genetic tools, Drosophila spermatocytes have provided an excellent system for exploring the mechanistic basis for the temporally programmed and precise spatially localized events of cytokinesis. Mutants defective in male meiotic cytokinesis can be easily identified in forward genetic screens by the production of multinucleate spermatids. In addition, the weak spindle assembly checkpoint in spermatocytes, which causes only a small delay of anaphase onset in the presence of unattached chromosomes, allows investigation of whether gene products required for spindle assembly and chromosome segregation are also involved in cytokinesis. Perhaps due to the large size of spermatocytes and the requirement for two rapid-fire rounds of division without intervening S or growth phases during meiosis, male meiotic mutants have also revealed much about molecular mechanisms underlying new membrane addition during cytokinesis. Finally, cell type-specific differences in the events that set up and complete cytokinesis are emerging from comparison of spermatocytes with cells undergoing mitosis either elsewhere in the organism or in tissue culture.

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Section: Discussionmentioning

confidence: 99%

What Drosophila spermatocytes tell us about the mechanisms underlying cytokinesis

Giansanti

Fuller

2012

Cytoskeleton

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“…Von Hippel–Lindau syndrome (VHL) is characterized by pheochromocytomas, renal agiomas, haemangioblastomas and renal cell carcinoma. The protein mutated in Von Hippel‐Lindau syndrome, pVHL, has recently been shown to be required for the recruitment of Alix and endobrevin to the midbody 105. These proteins interact with ESCRT‐1, which has been implicated in cytokinetic abscission 106, 107.…”

Section: Diseases Associated With Cytokinesis Failurementioning

confidence: 99%

“…These proteins interact with ESCRT‐1, which has been implicated in cytokinetic abscission 106, 107. Depletion of pVHL‐cell from retinal carcinoma cells caused chromosome instability and incomplete cytokinesis 105. Thus, the ploidy defects observed in VHL pathologies are likely due to misregulation of cytokinesis.…”

Section: Diseases Associated With Cytokinesis Failurementioning

confidence: 99%

Cytokinesis, ploidy and aneuploidy

Lacroix

Maddox

2011

The Journal of Pathology

119

102

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Cytokinesis is the last step of cell division that physically separates the daughter cells. As such, it ensures the proper inheritance of both nuclear and cytoplasmic contents. Accomplishment of cytokinesis in eukaryotes is dictated by several key events: establishment of the division plane, furrow ingression through contraction of an actomyosin ring and abscission via membrane fusion. Most mammalian somatic cells are diploid. Polyploidy can result from cytokinesis failure and may contribute to the development of pathologies such as cancer. However, polyploidy is essential for cellular differentiation and function in some contexts (eg hepatocytes, megakaryocytes and others). Consequently, the degree of ploidy and the achievement of cytokinesis must be tightly regulated throughout an organism and among different cell types. In this review we will highlight several examples of normal and pathological polyploidy, focusing on those caused by a controlled failure or dysregulation of cytokinesis, respectively. Last, we propose therapeutic routes to control cytokinesis to restore or block cell division.

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“…Among these potential interacting proteins, Dynamin2 attracted our attention, for previous study showed that Dynamin2 might coordinate membrane remodeling and actin filament dynamics during cell morphogenesis and cell migration [18]. In addition, Dynamin2 has been localized to midbodies during cytokinesis [19]. The interaction between NTKL and Dynamin2 was further confirmed by co-immunoprecipitation assay (Figure 6E).…”

Section: Resultsmentioning

confidence: 69%

Overexpression of N-terminal kinase like gene promotes tumorigenicity of hepatocellular carcinoma by regulating cell cycle progression and cell motility

et al. 2015

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Amplification and overexpression of CHD1L is one of the most frequent genetic alterations in hepatocellular carcinoma (HCC). Here we found that one of CHD1L downstream targets, NTKL, was frequently upregulated in HCC, which was significantly correlated with vascular invasion (P = 0.012) and poor prognosis (P = 0.050) of HCC. ChIP assay demonstrated the binding of CHD1L to the promoter region of NTKL. QRT-PCR study showed that the expression of NTKL positively correlated with CHD1L expression in both clinical samples and cell lines. Functional study found that NTKL had strong oncogenic roles, including increased cell growth, colony formation in soft agar, and tumor formation in nude mice. Further study found that NTKL could promote G1/S transition by decreasing P53 and increasing CyclinD1 expressions. NTKL overexpression could accelerate the mitotic exit and chromosome segregation, which led to the cytokinesis failure and subsequently induced apoptosis. NTKL also regulated cell motility by facilitating philopodia and lamellipodia formation through regulating F-actin reorganization and the phosphorylation of small GTPase Rac1/cdc42. Using co-IP and mass spectrometry approach, we identified the large GTPase dynamin2 as an interacting protein of NTKL, which might be responsible for the phenotype alterations caused by NTKL overexpression, such as cytokinesis failure, increased cell motility and abnormal of cell division.

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Von Hippel-Lindau gene product directs cytokinesis: a new tumor suppressor function

Cited by 12 publications

References 46 publications

What Drosophila spermatocytes tell us about the mechanisms underlying cytokinesis

What Drosophila spermatocytes tell us about the mechanisms underlying cytokinesis

Cytokinesis, ploidy and aneuploidy

Overexpression of N-terminal kinase like gene promotes tumorigenicity of hepatocellular carcinoma by regulating cell cycle progression and cell motility

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