MLL/WDR5 Complex Regulates Kif2A Localization to Ensure Chromosome Congression and Proper Spindle Assembly during Mitosis

Ali, Aamir; Veeranki, Sailaja Naga; Chinchole, Akash; Tyagi, Shweta

doi:10.1016/j.devcel.2017.05.023

Cited by 59 publications

(105 citation statements)

References 77 publications

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“…Curiously, free MLL C localizes in the cytoplasm and physical interactions with MLL N are required to transport it to the nucleus implying that sub-cellular localization of MLL C is governed by its association with MLL N [12,16]. Recently, we reported a novel function of MLL, where we observed that MLL localized to spindle apparatus to regulate spindle assembly and chromosome alignment during mitosis [17]. Interestingly, MLL C was the effector subunit in this non-canonical function as well, sufficient to rescue chromosome-misalignment phenotype caused by MLL RNAi.…”

Section: Introductionmentioning

confidence: 94%

“…We have previously reported that MLL localizes to spindle microtubules during mitosis [17]. To investigate further, we checked the localization of MLL in live cells in mitosis.…”

Section: Localization Of Mll Subunits In Mitosismentioning

confidence: 99%

“…MLL, though majorly nuclear, has been reported to localize to cytoplasm as well [16][17][18][19]. Curiously, free MLL C localizes in the cytoplasm and physical interactions with MLL N are required to transport it to the nucleus implying that sub-cellular localization of MLL C is governed by its association with MLL N [12,16].…”

Section: Introductionmentioning

confidence: 99%

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Novel sub-cellular localizations and intra-molecular interactions may define new functions of Mixed Lineage Leukemia protein

et al. 2018

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Mixed-lineage leukemia (MLL) protein is the best-characterized member of SET family of histone 3 lysine 4 methyltransferase, known for its transcriptional-activation role during development. mll gene rearrangements cause multiple kinds of aggressive leukemia in both children and adults. An important 'first' step in understanding the role of MLL in leukemogenesis would be to identify its localization throughout the cell cycle. In order to fully understand the breath of MLL functions in proliferating cells, we have analyzed its sub-cellular localization during the cell cycle. Our results show that MLL localizes to nucleolus and centrosome in interphase. During mitosis, it localizes to centrosomes and midbody in addition to previously reported spindle apparatus. Our results show that MLL N is required to translocate MLL C to the nucleolus. These finding suggest functional roles for MLL in nucleolus and mitosis. We also show how MLL-fusion proteins (MLL-FPs) localize to the same sub-cellular organelles like endogenous MLL. Our results indicate that MLL-fusion proteins may not only disturb the cell homeostasis by gain-of-function of the chimeric protein, but also by interfering with the functions of endogenous MLL. ARTICLE HISTORY

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Section: Introductionmentioning

confidence: 94%

“…We have previously reported that MLL localizes to spindle microtubules during mitosis [17]. To investigate further, we checked the localization of MLL in live cells in mitosis.…”

Section: Localization Of Mll Subunits In Mitosismentioning

confidence: 99%

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Novel sub-cellular localizations and intra-molecular interactions may define new functions of Mixed Lineage Leukemia protein

et al. 2018

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“…A growing number of studies have shown a strong connection between cytokinesis and ciliogenesis, as both processes are actin and microtubule dependent [19][20][21][22][23][24][25][26][27][28][29][30][31]. Recently, a study showed that the midbody hosts multiple proteins important for cilia assembly.…”

Section: Ccdc11 Is Essential For Maintaining Rhoa Protein Levels Indementioning

confidence: 99%

“…The master regulator of cytokinesis, RhoA, also localizes to the base of the cilium [28][29][30]. Recently, we and others discovered that the chromatin modifier WDR5 is also localized to the bases of cilia, the spindle microtubules and the midbody [19,21,31]. Further, intraflagellar transport proteins necessary for ciliogenesis and cilia maintenance are also critical for cleavage furrow ingression [22,23,[25][26][27].…”

Section: Ccdc11 Is Essential For Maintaining Rhoa Protein Levels Indementioning

confidence: 99%

The Heterotaxy Gene CCDC11 is Essential for Cytokinesis and Cell-Cell Adhesion via RhoA Regulation

Kulkarni

Stephenson

Amalraj

et al. 2018

Preprint

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RhoA is critical for cytokinesis and cell-cell adhesion. While we have made significant progress in identifying the regulators of RhoA, our understanding remains incomplete. In multiple patients with heterotaxy (Htx), a disorder of left-right (LR) patterning of the internal organs, mutations in CCDC11 were identified. In Xenopus, depletion of ccdc11 causes defects in LR patterning, recapitulating the patients' phenotype. Interestingly, with ccdc11 depletion, normally monociliated cells of the Left-Right Organizer (LRO) exhibited multiple cilia per cell.While investigating this multiciliated phenotype, we unexpectedly discovered that ccdc11 is critical for cytokinesis. In addition, CCDC11 depletion alters cell-cell adhesion with loss of junctional adhesion molecules.Based on these phenotypes, reminiscent of RhoA loss of function, we demonstrate that CCDC11 colocalizes with RhoA during cytokinesis and regulates total RhoA protein levels. In conclusion, CCDC11 surprisingly connects cytokinesis and LR patterning via RhoA regulation, providing a potential mechanism for disease pathogenesis. RESULTS AND DISCUSSION Ccdc11 is important in establishing left-right asymmetryThe embryo breaks bilateral symmetry beginning at the Left-Right Organizer (LRO) [1][2][3]. Here, a subset of cells with motile monocilia drive extracellular fluid towards the left, which is sensed by immotile monocilia [4][5][6].As a consequence, dand5 (Cerl2 in mouse, coco in frog), which is initially expressed bilaterally at the margin of the LRO, is repressed on the left [2,7,8]. Repression of dand5 leads to expression of pitx2 in the left lateral plate mesoderm [1,9,10]. Pitx2 drives asymmetric organogenesis such that the heart, which initiates as a midline tube, loops to the right while other organs like the gut also undergo asymmetric morphogenesis [11].Therefore, a signaling cascade including cilia driven extracellular fluid flow, dand5, and pitx2 establish laterality of internal organs such as the heart.CCDC11 plays a key role in establishing LR asymmetry [12][13][14][15]. A number of Htx patients have CCDC11 alleles, and depletion of ccdc11 causes LR patterning defects in zebrafish and Xenopus [12][13][14][15]. Consistent with these studies, we also show that ccdc11 is important for LR patterning in Xenopus. We depleted Ccdc11 using F0 CRISPR and examined cardiac looping ( Figure 1A). We found that embryos depleted of ccdc11 showed significant cardiac looping defects (~22%) compared to uninjected controls. In addition, overexpression of human CCDC11 also showed significant cardiac looping defects (~15%) compared to uninjected controls suggesting that precise regulation of CCDC11 levels is necessary for its proper function ( Figure 1A). To place CCDC11 in the LR patterning cascade, we next examined pitx2 and coco. Using a ccdc11 morpholino oligo (MO), we found that ccdc11 knockdown led to abnormal patterns of both pitx2 (~25%) and coco (~80%) (Figures 1B-C). Therefore, using either depletion strategy, F0 CRISPR or MO, ccdc11 depletion is critica...

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Kinesin family member 2A high expression correlates with advanced tumor stages and worse prognosis in non‐small cell lung cancer patients

Wang

2019

Clinical Laboratory Analysis

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractBackground: This present study was to explore the association of kinesin family member 2A (KIF2A) expression with clinicopathological features and survival profiles, and the effect of KIF2A on cell proliferation and chemosensitivity in non-small cell lung cancer (NSCLC). Methods:Tumor and paired adjacent specimens were collected from 380 patients with NSCLC underwent resection for immunohistochemistry assay of KIF2A expression. In vitro, the effect of KIF2A on cell proliferation, chemosensitivity to cisplatin/ vinorelbine was detected via KIF2A plasmids transfection into NCI-H1299 NSCLC cells.Results: Kinesin family member 2A expression was upregulated in tumor tissues compared with adjacent tissues, and tumor tissue KIF2A high expression was associated with higher pathological grade (P < .001), larger tumor size (P = .021), lymph node metastasis (P = .044), and increased tumor-node-metastasis stage (P = .001).As for survival profiles, disease-free survival (P < .001) and overall survival (P < .001) were worse in patients with KIF2A high expression compared with those with KIF2A low expression. Multivariate Cox's regression exhibited that KIF2A high expression was an independent predictive factor for lower DFS (P < .001) and OS (P < .001). In vitro, KIF2A promoted proliferation and decreased chemosensitivity to cisplatin but not vinorelbine in NCI-H1299 NSCLC cells. Conclusions:The correlation of KIF2A expression with tumor features, survival, and its cellular function implies its potential as a prognostic biomarker and a treatment target in NSCLC. K E Y W O R D Scell proliferation, chemosensitivity, clinical features, kinesin family member 2A, non-small cell lung cancer

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MLL/WDR5 Complex Regulates Kif2A Localization to Ensure Chromosome Congression and Proper Spindle Assembly during Mitosis

Cited by 59 publications

References 77 publications

Novel sub-cellular localizations and intra-molecular interactions may define new functions of Mixed Lineage Leukemia protein

Novel sub-cellular localizations and intra-molecular interactions may define new functions of Mixed Lineage Leukemia protein

The Heterotaxy Gene CCDC11 is Essential for Cytokinesis and Cell-Cell Adhesion via RhoA Regulation

Kinesin family member 2A high expression correlates with advanced tumor stages and worse prognosis in non‐small cell lung cancer patients

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