The Ki‐67 protein interacts with members of the heterochromatin protein 1 (HP1) family: a potential role in the regulation of higher‐order chromatin structure

Scholzen, Thomas; Endl, Elmar; Wohlenberg, Claudia; Sar, Sjaak van der; Cowell, Ian G.; Gerdes, Johannes; Singh, Prim B.

doi:10.1002/path.1016

Cited by 100 publications

(96 citation statements)

References 41 publications

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“…A myocyte mitotic index of 0.0014% in control hearts and 0.013% to 0.015% in diseased hearts was determined by confocal analysis. 2 Those initial data were confirmed and amplified in an autopsy study of human hearts 3 in which actively dividing cardiomyocytes (evidenced by Ki67 expression, a nuclear antigen expressed in dividing cells 4 ) resulted in mitotic indices of 0.08% and 0.03% in the regions adjacent to and distant from the infarcts, respectively. In principle, mitotic figures in the heart could arise from preformed cardiomyocytes released from cell cycle inhibition or from resident cardiomyocyte precursors or stem cells that become activated.…”

Section: Introductionmentioning

confidence: 83%

Stem cells in the heart: What's the buzz all about?—Part 1: Preclinical considerations

et al. 2008

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New approaches for cardiac repair have been enabled by the discovery that the heart contains its own reservoir of stem cells. These cells are positive for various stem/progenitor cell markers, are selfrenewing, and exhibit multilineage differentiation potential. Recently we developed a method for ex vivo expansion of cardiac-derived stem cells from human myocardial biopsies with a view to subsequent autologous transplantation for myocardial regeneration. Here we review the state of the cardiac stem cell field and our own work on cardiosphere-derived stem cells from human hearts. The first of this two-part review outlines emerging preclinical data on the application of cardiac stem cells. Part 2 continues with a discussion of other stem cell sources with clinical potential, a summary of the critical issues surrounding stem cell therapy (with an emphasis on the crucial issue of how cell transplantation may influence arrhythmias), our perception of clinical stem cell trials to date, and the issues facing the clinical application of cardiac stem cells.

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Section: Introductionmentioning

confidence: 83%

Stem cells in the heart: What's the buzz all about?—Part 1: Preclinical considerations

et al. 2008

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“…This is also supported by the finding that pKi-67 binds preferentially to supercoiled chromatin rather than to single-or doublestranded DNA (MacCallum and Hall 2000). Moreover, a recent study has demonstrated that the small non-histone heterochromatin protein 1 (HP1) interacts with the C-terminal portion of pKi-67 (Kametaka et al 2002;Scholzen et al 2002). Therefore, pKi-67 appears to be an intrinsic tracer that can be used to localize a well-defined heterochromatin domain in proliferating cells and to study its 3D organization.…”

Section: Discussionmentioning

confidence: 99%

Three-dimensional Organization of pKi-67: A Comparative Fluorescence and Electron Tomography Study Using Fluoronanogold

Cheutin¹,

O’Donohue²,

Beorchia

et al. 2003

J Histochem Cytochem.

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S U M M A R YThe monoclonal antibody (MAb) Ki-67 is routinely used in clinical studies to estimate the growth fraction of tumors. However, the role of pKi-67, the protein detected by the Ki-67 MAb, remains elusive, although some biochemical data strongly suggest that it might organize chromatin. To better understand the functional organization of pKi-67, we studied its three-dimensional distribution in interphase cells by confocal microscopy and electron tomography. FluoroNanogold, a single probe combining a dense marker with a fluorescent dye, was used to investigate pKi-67 organization at the optical and ultrastructural levels. Observation by confocal microscopy followed by 3D reconstruction showed that pKi-67 forms a shell around the nucleoli. Double labeling experiments revealed that pKi-67 co-localizes with perinucleolar heterochromatin. Electron microscopy studies confirmed this close association and demonstrated that pKi-67 is located neither in the fibrillar nor in the granular components of the nucleolus. Finally, spatial analyses by electron tomography showed that pKi-67 forms cords 250-300 nm in diameter, which are themselves composed of 30-50-nm-thick fibers. These detailed comparative in situ analyses strongly suggest the involvement of pKi-67 in the higher-order organization of perinucleolar chromatin. (J Histochem

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“…Besides its transportation function, the chromosome periphery may also play active roles in chromosome structure. As an example, the chromosome peripheral protein Ki-67 is involved in the formation of higherorder chromatin structures (Takagi et al, 1999;Kametaka et al, 2002;Scholzen et al, 2002;Saiwaki et al, 2005). In addition, it has been speculated that the chromosome periphery is involved in the progression of mitosis, possibly by participating in the protection and stabilization of the chromosomes.…”

Section: Introductionmentioning

confidence: 99%

Nucleolin functions in nucleolus formation and chromosome congression

Matsunaga

Takata

et al. 2007

Journal of Cell Science

120

124

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A complex structure, designated the chromosome periphery, surrounds each chromosome during mitosis. Although several proteins have been shown to localize to the chromosome periphery, their functions during mitosis remain unclear. Here, we used a combination of highresolution microscopy and RNA-interference-mediated depletion to study the functions of nucleolin, a nucleolar protein localized at the chromosome periphery, in interphase and mitosis. During mitosis, nucleolin was localized in the peripheral region including the vicinity of the outer kinetochore of chromosomes. Staining with an antibody specific for nucleolin phosphorylated by CDC2 revealed that nucleolin was also associated with the spindle poles from prometaphase to anaphase. Nucleolin depletion resulted in disorganization of the nucleoli at interphase. Furthermore, nucleolin-depleted cells showed a prolonged cell cycle with misaligned chromosomes and defects in spindle organization. The misaligned chromosomes showed syntelic kinetochore-microtubule attachments with reduced centromere stretching. Taken together, our results indicate that nucleolin is required for nucleolus formation, and is also involved in chromosome congression and spindle formation. Journal of Cell Science 2092Nucleolin is an abundant nucleolar protein localized in the DFCs and GCs of nucleoli (Biqqioqera et al., 1990). Nucleolin plays essential roles in rDNA transcription, rRNA maturation, ribosome assembly and nucleocytoplasmic transport (Ginisty et al., 1999;Srivastava and Pollard, 1999). As a multifunctional protein, nucleolin has also been proposed to be a nuclear matrix-binding protein (Gotzmann et al., 1997), to interact with telomerase (Khurts et al., 2004) and to be involved in the regulation of apoptosis (Mi et al., 2003), intestinal cell differentiation (Turck et al., 2006) and remodeling of nucleosomes (Angelov et al., 2006). Although many functions of nucleolin have been clarified, previous studies have fallen short of demonstrating its functions during mitosis.Nucleolin is highly phosphorylated (Olson et al., 1975;Rao et al., 1982) and its phosphorylation is highly regulated during the cell cycle (Peter et al., 1990;Morimoto et al., 2005). Extensive phosphorylation by casein kinase 2 (CK2) occurs at interphase and by CDC2 during mitosis (Peter et al., 1990), and this regulated phosphorylation of nucleolin probably regulates nucleolin functions during the cell cycle (Ginisty et al., 1999). It has been demonstrated that phosphorylation of nucleolin at interphase is correlated with active rRNA transcription (Suzuki et al., 1987). Despite a previous study describing the localization of nucleolin phosphorylated by CDC2 (Dranovsky et al., 2001), no information about its functions during mitosis has been obtained to date.Here, we demonstrate that nucleolin localizes to the nucleoli, which are located in the peripheral region including the vicinity of the outer kinetochore of chromosomes, in interphase nuclei and during mitosis. Staining with an antibody specific for nucle...

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The Ki‐67 protein interacts with members of the heterochromatin protein 1 (HP1) family: a potential role in the regulation of higher‐order chromatin structure

Cited by 100 publications

References 41 publications

Stem cells in the heart: What's the buzz all about?—Part 1: Preclinical considerations

Stem cells in the heart: What's the buzz all about?—Part 1: Preclinical considerations

Three-dimensional Organization of pKi-67: A Comparative Fluorescence and Electron Tomography Study Using Fluoronanogold

Nucleolin functions in nucleolus formation and chromosome congression

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