scholarly journals Chromosome clustering in mitosis by the nuclear protein Ki-67

2021 ◽  
Author(s):  
Konstantinos Stamatiou ◽  
Paola Vagnarelli
Keyword(s):  
Protein Phosphatase ◽  
Mitotic Chromosome ◽  
Nuclear Protein ◽  
Protein A ◽  
Mitotic Exit ◽  
Proliferating Cells ◽  
Ki 67 ◽  
Mitotic Entry ◽  
Long Time

Ki-67 is highly expressed in proliferating cells, a characteristic that made the protein a very important proliferation marker widely used in the clinic. However, the molecular functions and properties of Ki-67 remained quite obscure for a long time. Only recently important discoveries have shed some light on its function and shown that Ki-67 has a major role in the formation of mitotic chromosome periphery compartment, it is associated with protein phosphatase one (PP1) and regulates chromatin function in interphase and mitosis. In this review, we discuss the role of Ki-67 during cell division. Specifically, we focus on the importance of Ki-67 in chromosome individualisation at mitotic entry (prometaphase) and its contribution to chromosome clustering and nuclear remodelling during mitotic exit.

scholarly journals The Ki-67 and RepoMan mitotic phosphatases assemble via an identical, yet novel mechanism

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ganesan Senthil Kumar ◽  
Ezgi Gokhan ◽  
Sofie De Munter ◽  
Mathieu Bollen ◽  
Paola Vagnarelli ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Mitotic Chromosome ◽  
Cancer Therapeutics ◽  
Mitotic Exit ◽  
Protein Phosphatase 1 ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Ki 67 ◽  
Anaphase Onset

Ki-67 and RepoMan have key roles during mitotic exit. Previously, we showed that Ki-67 organizes the mitotic chromosome periphery and recruits protein phosphatase 1 (PP1) to chromatin at anaphase onset, in a similar manner as RepoMan (<xref ref-type="bibr" rid="bib2">Booth et al., 2014</xref>). Here we show how Ki-67 and RepoMan form mitotic exit phosphatases by recruiting PP1, how they distinguish between distinct PP1 isoforms and how the assembly of these two holoenzymes are dynamically regulated by Aurora B kinase during mitosis. Unexpectedly, our data also reveal that Ki-67 and RepoMan bind PP1 using an identical, yet novel mechanism, interacting with a PP1 pocket that is engaged only by these two PP1 regulators. These findings not only show how two distinct mitotic exit phosphatases are recruited to their substrates, but also provide immediate opportunities for the design of novel cancer therapeutics that selectively target the Ki-67:PP1 and RepoMan:PP1 holoenzymes.

Tissue Ki67 proliferative index expression and pathological changes in hemodialysis arteriovenous fistulae: Preliminary single-center results

2021 ◽  
pp. 112972982110154
Author(s):  
Raffaella Mauro ◽  
Cristina Rocchi ◽  
Francesco Vasuri ◽  
Alessia Pini ◽  
Anna Laura Croci Chiocchini ◽  
...  
Keyword(s):  
Morphological Changes ◽  
Hot Spot ◽  
Wall Thickening ◽  
Proliferating Cells ◽  
Ki 67 ◽  
Group A ◽  
The Mean ◽  
Set Up ◽  
Group B

Background: Arteriovenous fistula (AVF) for hemodialysis integrates outward remodeling with vessel wall thickening in response to drastic hemodynamic changes. Aim of this study is to determine the role of Ki67, a well-established proliferative marker, related to AVF, and its relationship with time-dependent histological morphologic changes. Materials and methods: All patients were enrolled in 1 year and stratified in two groups: (A) pre-dialysis patients submitted to first AVF and (B) patients submitted to revision of AVF. Morphological changes: neo-angiogenesis (NAG), myointimal thickening (MIT), inflammatory infiltrate (IT), and aneurysmatic fistula degeneration (AD). The time of AVF creation was recorded. A biopsy of native vein in Group A and of arterialized vein in Group B was submitted to histological and immunohistochemical (IHC) analysis. IHC for Ki67 was automatically performed in all specimens. Ki67 immunoreactivity was assessed as the mean number of positive cells on several high-power fields, counted in the hot spots. Results: A total of 138 patients were enrolled, 69 (50.0%) Group A and 69 (50.0%) Group B. No NAG or MIT were found in Group A. Seven (10.1%) Group A veins showed a mild MIT. Analyzing the Group B, a moderate-to-severe MIT was present in 35 (50.7%), IT in 19 (27.5%), NAG in 37 (53.6%); AD was present in 10 (14.5%). All AVF of Group B with the exception of one (1.4%) showed a positivity for Ki67, with a mean of 12.31 ± 13.79 positive cells/hot spot (range 0–65). Ki67-immunoreactive cells had a subendothelial localization in 23 (33.3%) cases, a myointimal localization in SMC in 35 (50.7%) cases. The number of positive cells was significantly correlated with subendothelial localization of Ki67 ( p = 0.001) and with NA ( p = 0.001). Conclusions: Native veins do not contain cycling cells. In contrast, vascular cell proliferation starts immediately after AVF creation and persists independently of the time the fistula is set up. The amount of proliferating cells is significantly associated with MIT and subendothelial localization of Ki67-immunoreactive cells, thus suggesting a role of Ki-67 index in predicting AVF failure.

Cell Proliferation in Retinal Transplants

1997 ◽  
Vol 6 (2) ◽  
pp. 141-148 ◽  
Author(s):  
Rajesh K. Sharma ◽  
Berndt Ehinger
Keyword(s):  
Cell Proliferation ◽  
Nuclear Protein ◽  
Subretinal Space ◽  
Ki 67 ◽  
Equivalent Age ◽  
Dividing Cells ◽  
Long Time ◽  
Graft Interface ◽  
Retinal Transplants ◽  
Mib 1

The MIB-1 antibody against a nuclear protein Ki-67 was used to study the proliferation of cells in the rabbit retinal transplants. Fragmented pieces of embryonic day 15 rabbit retinas were transplanted into the subretinal space of adult rabbits and allowed to survive for different times. Fragmented donor tissue starts organizing in rosettes 1 day after transplantation. The transplanted cells continue to proliferate in the host eye and their pattern of proliferation resembles that of normal developing retina, suggesting that the factors responsible for the proliferation pattern are preserved after transplantation. The dividing cells in metaphase line up in the luminal layers of the rosettes. Certain cells become postmitotic in the regions corresponding to the inner retina first, followed by the cells in the luminal layers of rosettes. Cells in the regions between the rosettes, corresponding to the inner nuclear layer, presumably the Müller cells, proliferate significantly for the equivalent age of postnatal day 2. Few cells in these regions proliferate for at least the equivalent age of postnatal day 11 in transplants. There is a layer of nonproliferating, degenerating cells in the transplant situated close to the host retina. However, some cells in this layer, situated at the host-graft interface, proliferate. These cells proliferate for a long time possibly indicating gliosis.

scholarly journals Automated Analysis of Proliferating Cells Spatial Organisation Predicts Prognosis in Lung Neuroendocrine Neoplasms

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4875
Author(s):  
Matteo Bulloni ◽  
Giada Sandrini ◽  
Irene Stacchiotti ◽  
Massimo Barberis ◽  
Fiorella Calabrese ◽  
...  
Keyword(s):  
Automated Analysis ◽  
Labelling Index ◽  
Neuroendocrine Neoplasms ◽  
Proliferating Cells ◽  
Ki 67 ◽  
Learning Framework ◽  
Diagnosis And Prognosis ◽  
Tumour Prognosis

Lung neuroendocrine neoplasms (lung NENs) are categorised by morphology, defining a classification sometimes unable to reflect ultimate clinical outcome. Subjectivity and poor reproducibility characterise diagnosis and prognosis assessment of all NENs. Here, we propose a machine learning framework for tumour prognosis assessment based on a quantitative, automated and repeatable evaluation of the spatial distribution of cells immunohistochemically positive for the proliferation marker Ki-67, performed on the entire extent of high-resolution whole slide images. Combining features from the fields of graph theory, fractality analysis, stochastic geometry and information theory, we describe the topology of replicating cells and predict prognosis in a histology-independent way. We demonstrate how our approach outperforms the well-recognised prognostic role of Ki-67 Labelling Index on a multi-centre dataset comprising the most controversial lung NENs. Moreover, we show that our system identifies arrangement patterns in the cells positive for Ki-67 that appear independently of tumour subtyping. Strikingly, the subset of these features whose presence is also independent of the value of the Labelling Index and the density of Ki-67-positive cells prove to be especially relevant in discerning prognostic classes. These findings disclose a possible path for the future of grading and classification of NENs.

scholarly journals Mitotic Exit Regulation through Distinct Domains within the Protein Kinase Cdc15

2003 ◽  
Vol 23 (14) ◽  
pp. 5018-5030 ◽  
Author(s):  
Allison J. Bardin ◽  
Monica G. Boselli ◽  
Angelika Amon
Keyword(s):  
Protein Kinase ◽  
Protein Phosphatase ◽  
Kinase Domain ◽  
Spindle Pole ◽  
Mitotic Exit ◽  
Spindle Pole Bodies ◽  
Mitotic Exit Network ◽  
Self Association ◽  
Premature Release

ABSTRACT The mitotic exit network (MEN), a Ras-like signaling cascade, promotes the release of the protein phosphatase Cdc14 from the nucleolus and is essential for cells to exit from mitosis in Saccharomyces cerevisiae. We have characterized the functional domains of one of the MEN components, the protein kinase Cdc15, and investigated the role of these domains in mitotic exit. We show that a region adjacent to Cdc15's kinase domain is required for self-association and for binding to spindle pole bodies and that this domain is essential for CDC15 function. Furthermore, we find that overexpression of CDC15 lacking the C-terminal 224 amino acids results in hyperactivation of MEN and premature release of Cdc14 from the nucleolus, suggesting that this domain within Cdc15 functions to inhibit MEN signaling. Our findings indicate that multiple modes of MEN regulation occur through the protein kinase Cdc15.

scholarly journals The intrinsically disorderly story of Ki-67

Open Biology ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 210120
Author(s):  
Lucy Remnant ◽  
Natalia Y. Kochanova ◽  
Caitlin Reid ◽  
Fernanda Cisneros-Soberanis ◽  
William C. Earnshaw
Keyword(s):  
Mitotic Chromosome ◽  
Clinical Importance ◽  
Molecular Function ◽  
Proliferating Cells ◽  
Ki 67 ◽  
Intrinsically Disordered ◽  
Disordered Structure ◽  
Nucleolar Proteins ◽  
Marker Proteins ◽  
Liquid Liquid Phase Separation

Ki-67 is one of the most famous marker proteins used by histologists to identify proliferating cells. Indeed, over 30 000 articles referring to Ki-67 are listed on PubMed. Here, we review some of the current literature regarding the protein. Despite its clinical importance, our knowledge of the molecular biology and biochemistry of Ki-67 is far from complete, and its exact molecular function(s) remain enigmatic. Furthermore, reports describing Ki-67 function are often contradictory, and it has only recently become clear that this proliferation marker is itself dispensable for cell proliferation. We discuss the unusual organization of the protein and its mRNA and how they relate to various models for its function. In particular, we focus on ways in which the intrinsically disordered structure of Ki-67 might aid in the assembly of the still-mysterious mitotic chromosome periphery compartment by controlling liquid–liquid phase separation of nucleolar proteins and RNAs.

scholarly journals The Role of the Polo Kinase Cdc5 in Controlling Cdc14 Localization

2003 ◽  
Vol 14 (11) ◽  
pp. 4486-4498 ◽  
Author(s):  
Rosella Visintin ◽  
Frank Stegmeier ◽  
Angelika Amon
Keyword(s):  
Protein Phosphatase ◽  
Regulatory Networks ◽  
Competitive Inhibitor ◽  
S Phase ◽  
Mitotic Exit ◽  
Late Anaphase ◽  
Mitotic Exit Network ◽  
Early Anaphase ◽  
The Relationship

In budding yeast, the protein phosphatase Cdc14 controls exit from mitosis. Its activity is regulated by a competitive inhibitor Cfi1/Net1, which binds to and sequesters Cdc14 in the nucleolus. During anaphase, Cdc14 is released from its inhibitor by the action of two regulatory networks. The Cdc Fourteen Early Anaphase Release (FEAR) network initiates Cdc14 release from Cfi1/Net1 during early anaphase, and the Mitotic Exit Network (MEN) promotes Cdc14 release during late anaphase. Here, we investigate the relationship among FEAR network components and propose an order in which they function to promote Cdc14 release from the nucleolus. Furthermore, we examine the role of the protein kinase Cdc5, which is a component of both the FEAR network and the MEN, in Cdc14 release from the nucleolus. We find that overexpression of CDC5 led to Cdc14 release from the nucleolus in S phase-arrested cells, which correlated with the appearance of phosphorylated forms of Cdc14 and Cfi1/Net1. Cdc5 promotes Cdc14 phosphorylation and, by stimulating the MEN, Cfi1/Net1 phosphorylation. Furthermore, we suggest that Cdc14 release from the nucleolus only occurs when Cdc14 and Cfi1/Net1 are both phosphorylated.

scholarly journals The cell proliferation-associated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins.

1993 ◽  
Vol 123 (3) ◽  
pp. 513-522 ◽  
Author(s):  
C Schlüter ◽  
M Duchrow ◽  
C Wohlenberg ◽  
M H Becker ◽  
G Key ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Nuclear Protein ◽  
Open Reading Frames ◽  
Growth Fraction ◽  
Proliferating Cells ◽  
Ki 67 ◽  
Nonhistone Proteins ◽  
Molecular Weights ◽  
Absolute Requirement

The antigen defined by mAb Ki-67 is a human nuclear protein the expression of which is strictly associated with cell proliferation and which is widely used in routine pathology as a "proliferation marker" to measure the growth fraction of cells in human tumors. Ki-67 detects a double band with apparent molecular weights of 395 and 345 kD in immunoblots of proteins from proliferating cells. We cloned and sequenced the full length cDNA, identified two differentially spliced isoforms of mRNA with open reading frames of 9,768 and 8,688 bp encoding for this cell proliferation-associated protein with calculated molecular weights of 358,761 D and 319,508 D, respectively. New mAbs against a bacterially expressed part and a synthetic polypeptide deduced from the isolated cDNA react with the native Ki-67 antigen, thus providing a circle of evidence that we have cloned the authentic Ki-67 antigen cDNA. The central part of the Ki-67 antigen cDNA contains a large 6,845-bp exon with 16 tandemly repeated 366-bp elements, the "Ki-67 repeats", each including a highly conserved new motif of 66 bp, the "Ki-67 motif", which encodes for the epitope detected by Ki-67. Computer analysis of the nucleic acid and the deduced amino acid sequence of the Ki-67 antigen confirmed that the cDNA encodes for a nuclear and short-lived protein without any significant homology to known sequences. Ki-67 antigen-specific antisense oligonucleotides inhibit the proliferation of IM-9 cell line cells, indicating that the Ki-67 antigen may be an absolute requirement for maintaining cell proliferation. We conclude that the Ki-67 antigen defines a new category of cell cycle-associated nuclear nonhistone proteins.

Role of PKC isozymes in water transport in toad urinary bladder

1991 ◽  
Vol 49 ◽  
pp. 302-303
Author(s):  
A.J. Mia ◽  
L.X. Oakford ◽  
T. Yorio
Keyword(s):  
Urinary Bladder ◽  
Apical Membrane ◽  
Membrane Surface ◽  
Protein A ◽  
Cell Types ◽  
Leukemic Cells ◽  
Toad Urinary Bladder ◽  
Pkc Isozymes ◽  
Antibody Labeling

Protein kinase C (PKC) isozymes, when activated, are translocated to particulate membrane fractions for transport to the apical membrane surface in a variety of cell types. Evidence of PKC translocation was demonstrated in human megakaryoblastic leukemic cells, and in cardiac myocytes and fibroblasts, using FTTC immunofluorescent antibody labeling techniques. Recently, we reported immunogold localizations of PKC subtypes I and II in toad urinary bladder epithelia, following 60 min stimulation with Mezerein (MZ), a PKC activator, or antidiuretic hormone (ADH). Localization of isozyme subtypes I and n was carried out in separate grids using specific monoclonal antibodies with subsequent labeling with 20nm protein A-gold probes. Each PKC subtype was found to be distributed singularly and in discrete isolated patches in the cytosol as well as in the apical membrane domains. To determine if the PKC isozymes co-localized within the cell, a double immunogold labeling technique using single grids was utilized.

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