Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence

AbstractCellular senescence is a stable cell cycle arrest that normal cells undergo after a finite number of divisions, in response to a variety of intrinsic and extrinsic stimuli. Although senescence is largely established and maintained by the p53/p21WAF1/CIP1 and pRB/p16INK4A tumour suppressor pathways, the downstream targets responsible for the stability of the growth arrest are not known. We have employed a stable senescence bypass assay in conditionally immortalised human breast fibroblasts (CL3EcoR) to investigate the role of the DREAM complex and its associated components in senescence. DREAM is a multi-subunit complex comprised of the MuvB core, containing LIN9, LIN37, LIN52, LIN54, and RBBP4, that when bound to p130, an RB1 like protein, and E2F4 inhibits cell cycle-dependent gene expression thereby arresting cell division. Phosphorylation of LIN52 at Serine 28 is required for DREAM assembly. Re-entry into the cell cycle upon phosphorylation of p130 leads to disruption of the DREAM complex and the MuvB core, associating initially to B-MYB and later to FOXM1 to form MMB and MMB-FOXM1 complexes respectively. Here we report that simultaneous expression of MMB-FOXM1 complex components efficiently bypasses senescence with LIN52, B-MYB, and FOXM1 as the crucial components. Moreover, bypass of senescence requires non-phosphorylated LIN52 that disrupts the DREAM complex, thereby indicating a central role for assembly of the DREAM complex in senescence.

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PPARr agonist, troglitazone induce growth arrest and apoptosis in MDA-MB-231 human breast cancer cell

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.13155 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 13155-13155

Author(s):

J. Park ◽

Y. Lee ◽

H. Yu ◽

M. Han ◽

B. Kim ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Human Breast Cancer ◽

Kinase Inhibitors ◽

Growth Arrest ◽

Ppar Gamma ◽

G1 Arrest ◽

Human Breast ◽

Ppar Γ ◽

Cycle Dependent

13155 Background: Estrogen receptor (ER)-negative breast carcinomas do not respond to hormone therapy, making their effective treatment very difficult. It is recently reported that peroxisome proliferator-activated receptor-gamma (PPAR-γ) has become a potential target for the prevention and treatment of human cancer. Therefore, PPAR-γ agonist, troglitazone has been extensively studied as a chemopreventive or therapeutic agent in several types of cancer. The purpose of this study was to assess whether troglitazone (TRO) would induce cell growth arrest and apoptosis in MDA-MB-231 (ER-negative) human breast cancer cells. Methods: Cytostatic/cytotoxic effects of troglitazone were measured with MTT assay. The cell cycle distribution was evaluated with flow cytometer. The expression of cyclin-dependent kinase inhibitors, p21, p27, and cell cycle dependent kinases was measured with Western blotting. Apoptotic cells were determined by Hoechst staining and TUNEL assay. Results: Troglitazone inhibited cell proliferation by inducing 65% G0/G1 arrest after 48 h. Accumulation of cells in G0/G1 was accompanied by a decrease of Rb protein phosphorylation associated with reduced activities of cell cycle dependent kinases (CDKs) such as cdk2 and cyclin D. Troglitazone increased the expression cyclin kinase inhibitors, p21 and p27 as MDA-MB-231 cell underwent G0/G1 arrest. Apoptotic effect by troglitazone demonstrated that apoptotic cells elevated from 2.5-fold of the control level at 10 uM, to 3.6-fold at 50 uM and to 4.7-fold at 75 uM. Conclusion: These results indicate that activation of PPAR-gamma with troglitazone induces apoptosis through cell cycle inhibition in estrogen receptor-negative breast cancer cell MDA-MB-231. PPAR-gamma therefore represents a putative molecular target for chemopreventive therapy or inhibition of breast cancer growth. No significant financial relationships to disclose.

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The role of MAP kinase in TPA-mediated cell cycle arrest of human breast cancer cells

Oncogene ◽

10.1038/sj.onc.1201485 ◽

1998 ◽

Vol 16 (1) ◽

pp. 131-139 ◽

Cited By ~ 68

Author(s):

Jacqueline Alblas ◽

Rivka Slager-Davidov ◽

Paul H Steenbergh ◽

John S Sussenbach ◽

Bart van der Burg

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Cycle Arrest

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Nitric oxide-induced cytostasis and cell cycle arrest of a human breast cancer cell line (MDA-MB-231): Potential role of cyclin D1

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.041603998 ◽

2001 ◽

Vol 98 (6) ◽

pp. 3583-3588 ◽

Cited By ~ 110

Author(s):

S. Pervin ◽

R. Singh ◽

G. Chaudhuri

Keyword(s):

Breast Cancer ◽

Nitric Oxide ◽

Cell Cycle ◽

Human Breast Cancer ◽

Potential Role ◽

Cancer Cell Line ◽

Human Breast Cancer Cell ◽

Human Breast ◽

Cycle Arrest

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Ser727/Tyr701-phosphorylated Stat1 is required for the regulation of c-Myc, cyclins, and p27Kip1 associated with ATRA-induced G0/G1 arrest of U-937 cells

Blood ◽

10.1182/blood-2002-10-3149 ◽

2003 ◽

Vol 102 (1) ◽

pp. 254-261 ◽

Cited By ~ 39

Author(s):

Anna Dimberg ◽

Inger Karlberg ◽

Kenneth Nilsson ◽

Fredrik Öberg

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Kinase Inhibitors ◽

Growth Arrest ◽

Myeloid Cells ◽

G1 Arrest ◽

Atra Treatment ◽

Cycle Arrest ◽

All Trans Retinoic Acid

Abstract All-trans retinoic acid (ATRA)—induced growth arrest of myeloid cells is associated with a sequential regulation of cyclins and cyclin-dependent kinase inhibitors (CKIs), which modulates the cell cycle machinery and inhibits the G1-S phase progression. ATRA treatment of myeloid cells induces up-regulation and tyrosine phosphorylation of Stat1, a member of the STAT (signal transducer and activator of transcription) transcription factor family that has been implicated in growth arrest in response to interferons. We have previously shown that ATRA-induced cell cycle arrest is dependent on tyrosinephosphorylated Stat1. In this study, we show that there is a basal level of Stat1 Ser727 phosphorylation in U-937 cells, which is transiently increased in response to ATRA treatment. Using Stat1Ser727Ala-expressing sublines, we provide evidence that Ser727 phosphorylation of Stat1 is required for ATRA-induced growth arrest. To shed further light on the role of Stat1 in ATRA-induced cell cycle arrest, cyclin and CKI expression was analyzed during ATRA treatment in U-937 sublines expressing Stat1Ser727Ala and Stat1Tyr701Phe. Our results show that Ser727/Tyr701-phosphorylated Stat1 plays a key role as a prerequisite for the ATRA-induced down-regulation of c-Myc; cyclins A, B, D2, D3, and E; and the simultaneous up-regulation of p27Kip1, associated with arrest in the G0/G1 phase of the cell cycle. (Blood. 2003;102:254-261)

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The Role of GADD34 (Growth Arrest and DNA Damage-Inducible Protein) in Regulating Apoptosis, Proliferation, and Protein Synthesis in Human Breast Cancer Cells

10.21236/ada427916 ◽

2004 ◽

Author(s):

Douglas C. Weiser

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Protein Synthesis ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Growth Arrest ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Inducible Protein

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Molecular Mechanisms of Thymoquinone as Anticancer agent

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323999201027225305 ◽

2020 ◽

Vol 23 ◽

Author(s):

Fatma Ismail Alhmied ◽

Ali Hassan Alammar ◽

Bayan Mohammed Alsultan ◽

Marooj Alshehri ◽

Faheem Hyder Pottoo

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Human Breast Cancer ◽

Phase Cell ◽

Cycle Phase ◽

Human Breast ◽

Cycle Arrest ◽

Phase Arrest ◽

Anti Cancer

Abstract:: Thymoquinone (TQ), the bioactive constituent of Nigella Sativa seeds is a well-known natural compound for the management of several types of cancers. The anti-cancer properties of thymoquinone are thought to be operated via intervening with various oncogenic pathways including cell cycle arrest, prevention of inflammation and oxidative stress, induction of invasion, metastasis, inhibition of angiogenesis, and apoptosis. As well as up-regulation and down-regulation of specific tumor suppressor genes and tumor promoting genes, respectively. Proliferation of various tumor cells is inhibited by TQ via induction of cell cycle arrest, disruption of the microtubule organization, and down regulating cell survival protein expression. TQ induces G1 phase cell cycle arrest in human breast cancer, colon cancer and osteosarcoma cells through inhibiting the activation of cyclin E or cyclin D and up-regulating p27and p21 a cyclin dependent kinase (Cdk) inhibitor. TQ concentration is a significant factor in targeting a particular cell cycle phase. While high concentration of TQ induced G2 phase arrest in human breast cancer (MCF-7) cells, low concentration causes S phase arrest. This review article provides mechanistic insights into the anti-cancer properties of thymoquinone.

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Role of Mis Localization of DNA Repair Factors in Cell Cycle Arrest

Biophysical Journal ◽

10.1016/j.bpj.2018.11.454 ◽

2019 ◽

Vol 116 (3) ◽

pp. 76a

Author(s):

Manasvita Vashisth ◽

Sangkyun Cho ◽

Dennis Discher

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Cell Cycle Arrest ◽

Cycle Arrest

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Matrix degradation and cell proliferation are coupled to promote invasion and escape from an engineered human breast microtumor

Integrative Biology ◽

10.1093/intbio/zyaa026 ◽

2021 ◽

Vol 13 (1) ◽

pp. 17-29

Author(s):

Emann M Rabie ◽

Sherry X Zhang ◽

Andreas P Kourouklis ◽

A Nihan Kilinc ◽

Allison K Simi ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Type I ◽

Matrix Degradation ◽

Human Breast ◽

Rate Of Invasion

Abstract Metastasis, the leading cause of mortality in cancer patients, depends upon the ability of cancer cells to invade into the extracellular matrix that surrounds the primary tumor and to escape into the vasculature. To investigate the features of the microenvironment that regulate invasion and escape, we generated solid microtumors of MDA-MB-231 human breast carcinoma cells within gels of type I collagen. The microtumors were formed at defined distances adjacent to an empty cavity, which served as an artificial vessel into which the constituent tumor cells could escape. To define the relative contributions of matrix degradation and cell proliferation on invasion and escape, we used pharmacological approaches to block the activity of matrix metalloproteinases (MMPs) or to arrest the cell cycle. We found that blocking MMP activity prevents both invasion and escape of the breast cancer cells. Surprisingly, blocking proliferation increases the rate of invasion but has no effect on that of escape. We found that arresting the cell cycle increases the expression of MMPs, consistent with the increased rate of invasion. To gain additional insight into the role of cell proliferation in the invasion process, we generated microtumors from cells that express the fluorescent ubiquitination-based cell cycle indicator. We found that the cells that initiate invasions are preferentially quiescent, whereas cell proliferation is associated with the extension of invasions. These data suggest that matrix degradation and cell proliferation are coupled during the invasion and escape of human breast cancer cells and highlight the critical role of matrix proteolysis in governing tumor phenotype.

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Cellular Senescence in Liver Disease and Regeneration

Seminars in Liver Disease ◽

10.1055/s-0040-1722262 ◽

2021 ◽

Author(s):

Sofia Ferreira-Gonzalez ◽

Daniel Rodrigo-Torres ◽

Victoria L. Gadd ◽

Stuart J. Forbes

Keyword(s):

Cell Cycle ◽

Liver Disease ◽

Cell Cycle Arrest ◽

Genomic Instability ◽

Cellular Senescence ◽

Cell Populations ◽

Cycle Arrest ◽

Relevant Role ◽

Extent Of Damage

AbstractCellular senescence is an irreversible cell cycle arrest implemented by the cell as a result of stressful insults. Characterized by phenotypic alterations, including secretome changes and genomic instability, senescence is capable of exerting both detrimental and beneficial processes. Accumulating evidence has shown that cellular senescence plays a relevant role in the occurrence and development of liver disease, as a mechanism to contain damage and promote regeneration, but also characterizing the onset and correlating with the extent of damage. The evidence of senescent mechanisms acting on the cell populations of the liver will be described including the role of markers to detect cellular senescence. Overall, this review intends to summarize the role of senescence in liver homeostasis, injury, disease, and regeneration.

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