The Ki-67 Protein: Fascinating Forms and an Unknown Function

doi:10.1006/excr.2000.4888

Experimental Cell Research

Volume 257, Issue 2, 15 June 2000, Pages 231-237

https://doi.org/10.1006/excr.2000.4888 Get rights and content

Abstract

The Ki-67 protein is a nuclear and nucleolar protein, which is tightly associated with somatic cell proliferation. Antibodies raised against the human Ki-67 protein paved the way for the immunohistological assessment of cell proliferation, particularly useful in numerous studies on the prognostic value of cell growth in clinical samples of human neoplasms. The primary structure revealed potential phosphorylation site for a range of essential kinases, PEST sequences, and a forkhead-associated domain, which are features present in a variety of cell-cycle-regulating proteins, but information about the position of the Ki-67 protein within the protein network that drives the cell cycle remained scarce. There is now evidence that posttranslational modifications based on phosphorylation by cdc2 kinase and PKC accompany the remarkable redistribution of the Ki-67 protein from the interior of the nucleus to the perichromosomal layer during mitosis and vice versa. The discovery of Ki-67 equivalents in other species is advantageous for a precise and cross-species investigation of the structural requirements for its yet unknown function. The recently published data add new pieces to the challenging puzzle of this multifaceted protein, which are waiting to be put together.

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Neurogenesis is a process of generating neural stem cells (NSCs) as functional neurons can be decreased after chemotherapy treatments. Methotrexate (MTX) is a folate antagonist that is used for cancer treatment but has negative effects, including oxidative stress, neuronal apoptosis and cognitive impairments. Hesperidin (Hsd), a flavonoid found in citrus fruits, has antioxidant and neuroprotection properties. This study investigated whether Hsd could attenuate impairments of hippocampal neural stem cells related to apoptosis induced by MTX. Spraque-Dawley rats (n = 24) were divided into 4 groups: (1) Vehicle group received propylene glycol (21 days) and 0.9% normal saline (day 8 and 15), (2) Hsd group received 100 mg/kg (21 days), (3) MTX group received 75 mg/kg (days 8 and 15) and (4) MTX+Hsd group received MTX, 75 mg/kg (day 8 and 15) and Hsd 100 mg/kg (21 days). Our results showed that MTX decreased hippocampal neural stem cells including SRY (sex determining region Y)-box 2 (SOX2) and nestin. MTX diminished vascular related (VR) Ki-67 positive cells in the hippocampus but not non-vascular related (NVR) Ki-67. Additionally, MTX reduced SOX2, nestin, postsynaptic density protein 95 (PSD-95) and B-cell lymphoma-2 family of proteins (Bcl-2), whereas Bax and caspase-3 were enhanced in the hippocampal tissues. Interestingly, co-treatment with Hsd and MTX revealed upregulation of SOX2, nestin and VR Ki-67 positive cells as well as elevated SOX2, nestin, PSD-95 and Bcl-2 proteins. Moreover, receiving both Hsd and MTX significantly suppressed increased Bax and caspase-3. These results confirm that Hsd can ameliorate MTX-induced impairments of hippocampal NSC proliferation and neuronal apoptosis.
The endometrial response to modulation of ligand-progesterone receptor pathways is reversible
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Citation Excerpt :
In this study, we utilized Ki67 as a reliable maker to assess endometrial cell proliferation (16, 34). It is a nuclear antigen present only in proliferating cells except in the G0 phase of the cell cycle (35, 36). Progesterone receptor modulators have been shown to reduce cell proliferation, but no data following cessation of PRM treatment are available (16, 37).
To study the impact of the progesterone receptor modulator (PRM), ulipristal acetate (UPA), on endometrial morphology and function.
Cross-sectional.
University Research Institute.
Endometrial biopsies from 16 patients with heavy menstrual bleeding with a structurally normal uterus or in association with structural abnormalities identified on radiological imaging (fibroids, adenomyosis or a combination of fibroids and adenomyosis).
Participants received UPA (5 mg once daily) for three 12-week courses, each separated by 4 weeks without treatment.
Gene expression by real-time quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and digital image analysis were analyzed to investigate the endometrial impact of modulation of progesterone receptor pathways upon expression of steroid receptors, steroid metabolizing enzymes, cell proliferation, and progesterone-regulated genes in the same patients at 3 time points: before, during, and after discontinuation of PRM treatment.
Ulipristal acetate treatment resulted in increased messenger ribonucleic acid (mRNA) levels of steroid receptors compared with pretreatment secretory endometrium; decreased mRNA levels of 17- and 11-beta-hydroxysteroid dehydrogenases compared with pretreatment proliferative endometrium and pretreatment secretory endometrium; reduced cell proliferation compared with pretreatment proliferative endometrium; and altered mRNA levels of progesterone-regulated genes. A strong consistency between immunohistochemistry-digital image analysis and real-time quantitative reverse transcription polymerase chain reaction results was evident. Alterations in the mRNA levels and endometrial morphology returned to a pretreatment phenotype after the cessation of PRM exposure.
The endometrial impact of the modulation of progesterone receptor pathways with PRM (UPA) treatment is reversible.
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La respuesta endometrial a la modulación de las vías de ligando-progesterona es reversible.
Estudiar el impacto del modulador de receptor de progesterona (PRM) y el acetato de ulipristal (UPA) en la morfología endometrial y su función.
Transversal.
Instituto universitario de investigación.
Biopsias endometriales de 16 pacientes con abundante sangrado menstrual y útero estructuralmente normal o asociadas con anormalidades estructurales identificadas con imágenes de radiología (fibromas, adenomiosis o una combinación de fibromas y adenomiosis).
Las participantes recibieron UPA (5 mg una vez al día) por tres cursos de 12 de semanas, cada uno separado de 4 semanas sin tratamiento.
Se analizaron la expresión de genes por medio de reacción en cadena de la polimerasa reversa cuantitativa en tiempo real, inmunohistoquímica y análisis digital de imágenes para investigar el impacto de la vía de modulación del receptor de la progesterona sobre la expresión de receptores esteroideos, enzimas metabólicas esteroideas, proliferación celular y genes reguladores de progesterona en las mismas paciente, en 3 puntos de tiempo: antes, durante y después de descontinuar el tratamiento con PRM.
El tratamiento con acetato de ulipristal resultó en un incremento de los niveles de ácido ribonucleico mensajero (mRNA) de los receptores esteroideos comparado con el endometrio secretor pretratamiento; niveles disminuidos de mRNA de la 17- y 11-beta-hidroxiesteroide dehidrogenasa comparado con el endometrio proliferativo pretratamiento; y niveles alterados de mRNA de genes reguladores de progesterona. Fue evidente una fuerte consistencia en los resultados entre el análisis inmunohistoquímico-imágenes digitales y la reacción en cadena de la polimerasa reversa cuantitativa en tiempo real. Las alteraciones en los niveles de mRNA y la morfología endometrial regresaron al fenotipo pretratamiento después del cese a la exposición de PRM.
El impacto endometrial de las vías de modulación del receptor de progesterona con el tratamiento PRM (UPA) es reversible.
Deep learning for the standardized classification of Ki-67 in vulva carcinoma: A feasibility study
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The aim of this study is to demonstrate the feasibility of automatic classification of Ki-67 histological immunostainings in patients with squamous cell carcinoma of the vulva using a deep convolutional neural network (dCNN).
For evaluation of the dCNN, we used 55 well characterized squamous cell carcinomas of the vulva in a tissue microarray (TMA) format in this retrospective study. The tumor specimens were classified in 3 different categories C1 (0–2%), C2 (2–20%) and C3 (>20%), representing the relation of the number of KI-67 positive tumor cells to all cancer cells on the TMA spot. Representative areas of the spots were manually labeled by extracting images of 351 × 280 pixels. A dCNN with 13 convolutional layers was used for the evaluation. Two independent pathologists classified 45 labeled images in order to compare the dCNN's results to human readouts.
Using a small labeled dataset with 1020 images with equal distribution among classes, the dCNN reached an accuracy of 90.9% (93%) for the training (validation) data. Applying a larger dataset with additional 1017 labeled images resulted in an accuracy of 96.1% (91.4%) for the training (validation) dataset. For the human readout, there were no significant differences between the pathologists and the dCNN in Ki-67 classification results.
The dCNN is capable of a standardized classification of Ki-67 staining in vulva carcinoma; therefore, it may be suitable for quality control and standardization in the assessment of tumor grading.
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Forty-four patients with LGMCP (55% male, median age 61) were identified. The median Ki67 score and hotspot Ki67 score was 15% (1–70) and 50% (1–90), respectively. On univariate analysis, average Ki67 and hotspot Ki67 were not predictive of PFS when analyzed as continuous normalized values (HR 1.0, p = 0.79 and HR 1.1, p = 0.38, respectively) or as categorical values when stratified by the median (HR 0.9, p = 0.67 and HR 1.0, p = 0.93). This remained true on multivariate analysis when stratified for peritoneal cancer index, CEA, and completeness of cytoreduction score for both normalized Ki67 and hotspot Ki67 (HR 0.9 [95% CI 0.8–1.3], p = 0.94 and HR 1.04 [95% CI 0.8–1.3], p = 0.73, respectively).
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¹: To whom correspondence and reprint requests should be addressed at Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany. Fax: +49-4537/188-724. E-mail: [email protected].

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MinireviewThe Ki-67 Protein: Fascinating Forms and an Unknown Function

Abstract

Exp. Cell Res.

TIBS

Curr. Opin. Cell Biol.

Curr. Opin. Cell Biol.

Curr. Opin. Cell Biol.

Micron

Exp. Cell Res.

J. Biol. Chem.

Exp. Cell Res.

FEBS Lett.

Curr. Biol.

Cell

Cell

Cell

Molecular characterization of the gene locus of the human cell proliferation-associated nuclear protein defined by monoclonal antibody Ki-67

Cell Prolif.

Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation

Int. J. Cancer

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

J. Cell Biol.

Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67

Am. J. Pathol.

Post-translational modifications of the Ki-67 protein coincide with two major check points during mitosis

J. Cell. Physiol.

Amino acid sequences common to rapidly degraded proteins: The PEST hypothesis

Science

Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67

J. Immunol.

The Ki-67 protein: From the known and the unknown

J. Cell. Physiol.

Growth fractions in malignant non-Hodgkin's lymphomas (NHL) as determined in situ with the monoclonal antibody Ki-67

Hematol. Oncol.

Little missed markers and Ki-67

Lab. Invest.

The prognostic value of Ki67 immunostaining in non-Hodgkin's lymphoma

J. Pathol.

Monoclonal antibody Ki-67: Its use in histopathology

Histopathology

Prognostic value of MIB-1 score, p53, EGFr, mitotic index and papillary status in primary superficial (Stage pTa/T1) bladder cancer: A prospective comparative study

Eur. Urol.

MIB-1 labelling index is an independent prognostic marker in primary breast cancer

Br. J. Cancer

Sequence requirements for synthetic peptide-mediated translocation to the nucleus

Mol. Cell Biol.

Nuclear import: A tale of two sites

Curr. Biol.

Minireview
The Ki-67 Protein: Fascinating Forms and an Unknown Function