Редактирование: FOXM1 (раздел)

==Publications==

{{medline-entry
|title=Sirtuin 6 deficiency induces endothelial cell senescence via downregulation of forkhead box M1 expression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33171439
|abstract=Cellular senescence of endothelial cells causes vascular dysfunction, promotes atherosclerosis, and contributes to the development of age-related vascular diseases. Sirtuin 6 ([[SIRT6]]), a conserved NAD -dependent protein deacetylase, has beneficial effects against aging, despite the fact that its functional mechanisms are largely uncharacterized. Here, we show that [[SIRT6]] protects endothelial cells from senescence. [[SIRT6]] expression is progressively decreased during both oxidative stress-induced senescence and replicative senescence. [[SIRT6]] deficiency leads to endothelial dysfunction, growth arrest, and premature senescence. Using genetically engineered endothelial cell-specific [[SIRT6]] knockout mice, we also show that down-regulation of [[SIRT6]] expression in endothelial cells exacerbates vascular aging. Expression microarray analysis demonstrated that [[SIRT6]] modulates the expression of multiple genes involved in cell cycle regulation. Specifically, [[SIRT6]] appears to regulate the expression of forkhead box M1 ([[FOXM1]]), a critical transcription factor for cell cycle progression and senescence. Overexpression of [[FOXM1]] ameliorates [[SIRT6]] deficiency-induced endothelial cell senescence. In this work, we demonstrate the role of [[SIRT6]] as an anti-aging factor in the vasculature. These data may provide the basis for future novel therapeutic approaches against age-related vascular disorders.

|keywords=* FOXM1
* SIRT6
* cell cycle
* endothelial cell
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695388
}}
{{medline-entry
|title=Upregulation of [[FOXM1]] leads to diminished drug sensitivity in myeloma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30463534
|abstract=Following up on previous work demonstrating the involvement of the transcription factor forkhead box M1 ([[FOXM1]]) in the biology and outcome of a high-risk subset of newly diagnosed multiple myeloma (nMM), this study evaluated whether [[FOXM1]] gene expression may be further upregulated upon tumor recurrence in patients with relapsed multiple myeloma (rMM). Also assessed was the hypothesis that increased levels of [[FOXM1]] diminish the sensitivity of myeloma cells to commonly used myeloma drugs, such as the proteasome inhibitor bortezomib (Bz) and the DNA intercalator doxorubicin (Dox). [[FOXM1]] message was evaluated in 88 paired myeloma samples from patients with nMM and rMM, using gene expression microarrays as measurement tool. Sources of differential gene expression were identified and outlier analyses were performed using statistical methods. Two independent human myeloma cell lines (HMCLs) containing normal levels of [[FOXM1]] ([[FOXM1]] ) or elevated levels of lentivirus-encoded [[FOXM1]] ([[FOXM1]] ) were employed to determine [[FOXM1]]-dependent changes in cell proliferation, survival, efflux-pump activity, and drug sensitivity. Levels of retinoblastoma (Rb) protein were determined with the assistance of Western blotting. Upregulation of [[FOXM1]] occurred in 61 of 88 (69%) patients with rMM, including 4 patients that exhibited > 20-fold elevated expression peaks. Increased [[FOXM1]] levels in [[FOXM1]]  myeloma cells caused partial resistance to Bz (1.9-5.6 fold) and Dox (1.5-2.9 fold) in vitro, using [[FOXM1]]  myeloma as control. Reduced sensitivity of [[FOXM1]]  cells to Bz was confirmed in vivo using myeloma-in-mouse xenografts. [[FOXM1]]-dependent regulation of total and phosphorylated Rb agreed with a working model of myeloma suggesting that [[FOXM1]] governs both chromosomal instability (CIN) and E2F-dependent proliferation, using a mechanism that involves interaction with NIMA related kinase 2 ([[NEK2]]) and cyclin dependent kinase 6 (CDK6), respectively. These findings enhanced our understanding of the emerging [[FOXM1]] genetic network in myeloma and provided preclinical support for the therapeutic targeting of the [[FOXM1]]-[[NEK2]] and CDK4/6-Rb-E2F pathways using small-drug CDK and [[NEK2]] inhibitors. Clinical research is warranted to assess whether this approach may overcome drug resistance in [[FOXM1]]  myeloma and, thereby, improve the outcome of patients in which the transcription factor is expressed at high levels.
|mesh-terms=* Animals
* Antineoplastic Agents
* Bortezomib
* Cell Line, Tumor
* Cell Proliferation
* Cell Survival
* Doxorubicin
* Drug Resistance
* Drug Tolerance
* Forkhead Box Protein M1
* Gene Expression Profiling
* Gene Expression Regulation, Neoplastic
* Humans
* Mice, Inbred NOD
* Mice, Knockout
* Mice, SCID
* Multiple Myeloma
* Up-Regulation
* Xenograft Model Antitumor Assays
|keywords=* Cellular senescence
* Plasma-cell neoplasm
* Small-drug inhibitor
* Targeted cancer therapy
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249818
}}
{{medline-entry
|title=Preclinical characterization of abemaciclib in hormone receptor positive breast cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29050219
|abstract=Abemaciclib is an ATP-competitive, reversible kinase inhibitor selective for [[CDK4]] and [[CDK6]] that has shown antitumor activity as a single agent in hormone receptor positive (HR ) metastatic breast cancer in clinical trials. Here, we examined the mechanistic effects of abemaciclib treatment using [i]in vitro[/i] and [i]in vivo[/i] breast cancer models. Treatment of estrogen receptor positive (ER ) breast cancer cells with abemaciclib alone led to a decrease in phosphorylation of Rb, arrest at G1, and a decrease in cell proliferation. Moreover, abemaciclib exposure led to durable inhibition of pRb, TopoIIα expression and DNA synthesis, which were maintained after drug removal. Treatment of ER  breast cancer cells also led to a senescence response as indicated by accumulation of β-galactosidase, formation of senescence-associated heterochromatin foci, and a decrease in [[FOXM1]] positive cells. Continuous exposure to abemaciclib altered breast cancer cell metabolism and induced apoptosis. In a xenograft model of ER  breast cancer, abemaciclib monotherapy caused regression of tumor growth. Overall these data indicate that abemaciclib is a [[CDK4]] and [[CDK6]] inhibitor that, as a single agent, blocks breast cancer cell progression, and upon longer treatment can lead to sustained antitumor effects through the induction of senescence, apoptosis, and alteration of cellular metabolism.

|keywords=* abemaciclib
* apoptosis
* cell cycle
* hormone receptor positive breast cancer
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642494
}}
{{medline-entry
|title=Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28920919
|abstract=Inadequate pancreatic β cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human β cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of β cell proliferation in human islets. We found that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human β cell proliferation in juvenile but not adult islets. This age-dependent responsiveness does not reflect loss of GLP-1R signaling in adult islets, since Ex-4 treatment stimulated insulin secretion by both juvenile and adult human β cells. We show that the mitogenic effect of Ex-4 requires calcineurin/nuclear factor of activated T cells (NFAT) signaling. In juvenile islets, Ex-4 induced expression of calcineurin/NFAT signaling components as well as target genes for proliferation-promoting factors, including [[NFATC1]], [[FOXM1]], and [[CCNA1]]. By contrast, expression of these factors in adult islet β cells was not affected by Ex-4 exposure. These studies reveal age-dependent signaling mechanisms regulating human β cell proliferation, and identify elements that could be adapted for therapeutic expansion of human β cells.
|mesh-terms=* Adult
* Aging
* Animals
* Calcineurin
* Cyclin A1
* Exenatide
* Female
* Forkhead Box Protein M1
* Glucagon-Like Peptide 1
* Glucagon-Like Peptide-1 Receptor
* Humans
* Insulin
* Insulin Secretion
* Insulin-Secreting Cells
* Male
* Mice, Inbred NOD
* Middle Aged
* NFATC Transcription Factors
* Peptides
* Signal Transduction
* Venoms

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617654
}}
{{medline-entry
|title=[[FOXM1]] regulates proliferation, senescence and oxidative stress in keratinocytes and cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27385468
|abstract=Several transcription factors, including the master regulator of the epidermis, p63, are involved in controlling human keratinocyte proliferation and differentiation. Here, we report that in normal keratinocytes, the expression of [[FOXM1]], a member of the Forkhead superfamily of transcription factors, is controlled by p63. We observe that, together with p63, [[FOXM1]] strongly contributes to the maintenance of high proliferative potential in keratinocytes, whereas its expression decreases during differentiation, as well as during replicative-induced senescence. Depletion of [[FOXM1]] is sufficient to induce keratinocyte senescence, paralleled by an increased ROS production and an inhibition of ROS-scavenger genes (SOD2, [[CAT]], [[GPX2]], PRDX). Interestingly, [[FOXM1]] expression is strongly reduced in keratinocytes isolated from old human subjects compared with young subjects. [[FOXM1]] depletion sensitizes both normal keratinocytes and squamous carcinoma cells to apoptosis and ROS-induced apoptosis. Together, these data identify [[FOXM1]] as a key regulator of ROS in normal dividing epithelial cells and suggest that squamous carcinoma cells may also use [[FOXM1]] to control oxidative stress to escape premature senescence and apoptosis.
|mesh-terms=* Carcinoma, Squamous Cell
* Cell Death
* Cell Differentiation
* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* Forkhead Box Protein M1
* Humans
* Keratinocytes
* Oxidative Stress
* Reactive Oxygen Species
* Skin Aging
|keywords=* FOXM1
* head and neck cancer
* oxidative stress
* p63
* senescence
* skin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993337
}}
{{medline-entry
|title=[[MELK]]-T1, a small-molecule inhibitor of protein kinase [[MELK]], decreases DNA-damage tolerance in proliferating cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26431963
|abstract=Maternal embryonic leucine zipper kinase ([[MELK]]), a serine/threonine protein kinase, has oncogenic properties and is overexpressed in many cancer cells. The oncogenic function of [[MELK]] is attributed to its capacity to disable critical cell-cycle checkpoints and reduce replication stress. Most functional studies have relied on the use of siRNA/shRNA-mediated gene silencing. In the present study, we have explored the biological function of [[MELK]] using [[MELK]]-T1, a novel and selective small-molecule inhibitor. Strikingly, [[MELK]]-T1 triggered a rapid and proteasome-dependent degradation of the [[MELK]] protein. Treatment of MCF-7 (Michigan Cancer Foundation-7) breast adenocarcinoma cells with [[MELK]]-T1 induced the accumulation of stalled replication forks and double-strand breaks that culminated in a replicative senescence phenotype. This phenotype correlated with a rapid and long-lasting ataxia telangiectasia-mutated (ATM) activation and phosphorylation of checkpoint kinase 2 (CHK2). Furthermore, [[MELK]]-T1 induced a strong phosphorylation of p53 (cellular tumour antigen p53), a prolonged up-regulation of p21 (cyclin-dependent kinase inhibitor 1) and a down-regulation of [[FOXM1]] (Forkhead Box M1) target genes. Our data indicate that [[MELK]] is a key stimulator of proliferation by its ability to increase the threshold for DNA-damage tolerance (DDT). Thus, targeting [[MELK]] by the inhibition of both its catalytic activity and its protein stability might sensitize tumours to DNA-damaging agents or radiation therapy by lowering the DNA-damage threshold. 
|mesh-terms=* Apoptosis
* Ataxia Telangiectasia Mutated Proteins
* Azepines
* Benzamides
* Breast Neoplasms
* Cell Line, Tumor
* Cell Proliferation
* DNA Damage
* Enzyme Inhibitors
* Female
* Forkhead Box Protein M1
* Forkhead Transcription Factors
* Gene Expression Regulation, Neoplastic
* Humans
* MCF-7 Cells
* Protein-Serine-Threonine Kinases
|keywords=* chemical biology
* deoxyribonucleic acid (DNA) damage response
* maternal embryonic leucine zipper kinase (MELK) kinase
* senescence
* small molecule inhibitors
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643329
}}
{{medline-entry
|title=Increased [[FOXM1]] expression can stimulate DNA repair in normal hepatocytes in vivo but also increases nuclear foci associated with senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25477198
|abstract=[[FOXM1]] is a transcription factor that has been shown to promote cell proliferation in many tissues during early development and high cell turnover tissues in adults. In a number of tumour cell lines, enrichment of [[FOXM1]] has been shown to reduce the DNA damage response (DDR) and induction of senescence by a range of DNA-damaging agents, suggesting a role for the protein in DNA repair. Endogenous [[FOXM1]] is expressed at detectable levels in hepatocytes of mice up to 2 weeks of age, but not in older mice. The aim of this investigation has been to better understand the role of the protein in DDR in normal cells in vivo. Mice with artificially prolonged elevated [[FOXM1]] expression in hepatocytes, were exposed to alkylating diethylnitrosamine. [[FOXM1]]-enriched mice had dampened DDR after treatment with this alkylating agent, which was consistent with observed increase in expression of genes involved in DNA repair. Paradoxically, mice with [[FOXM1]] expression, within weeks after exposure to the DNA-damaging agent, had increased levels of potentially senescent hepatocytes with large nuclear foci, containing 53BP1. Similarly, spontaneous accumulation of these cells seen with normal ageing in mice was increased with [[FOXM1]] enrichment. Despite its known abilities to promote proliferation and DNA repair, and to reduce ROS, enrichment of [[FOXM1]], as with other oncoproteins, may cause increased persistent DNA lesions and/or senescence in normal murine hepatocytes.
|mesh-terms=* Aging
* Animals
* Cell Nucleus
* DNA Repair
* Forkhead Box Protein M1
* Forkhead Transcription Factors
* Hepatocytes
* Mice
* Mice, Inbred C57BL

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522743
}}
{{medline-entry
|title=Cellular senescence and aging: the role of B-[[MYB]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24981831
|abstract=Cellular senescence is a stable cell cycle arrest, caused by insults, such as: telomere erosion, oncogene activation, irradiation, DNA damage, oxidative stress, and viral infection. Extrinsic stimuli such as cell culture stress can also trigger this growth arrest. Senescence is thought to have evolved as an example of antagonistic pleiotropy, as it acts as a tumor suppressor mechanism during the reproductive age, but can promote organismal aging by disrupting tissue renewal, repair, and regeneration later in life. The mechanisms underlying the senescence growth arrest are broadly considered to involve p16(INK4A) -pRB and p53-p21(CIP1/WAF1/SDI1) tumor suppressor pathways; but it is not known what makes the senescence arrest stable and what the critical downstream targets are, as they are likely to be key to the establishment and maintenance of the senescent state. [[MYB]]-related protein B (B-[[MYB]]/[[MYB]]L2), a member of the myeloblastosis family of transcription factors, has recently emerged as a potential candidate for regulating entry into senescence. Here, we review the evidence which indicates that loss of B-[[MYB]] expression has an important role in causing senescence growth arrest. We discuss how B-[[MYB]] acts, as the gatekeeper, to coordinate transit through the cell cycle, in conjunction with the multivulval class B (MuvB) complex and [[FOXM1]] transcription factors. We also evaluate the evidence connecting B-[[MYB]] to the mTOR nutrient signaling pathway and suggest that inhibition of this pathway leading to an extension of healthspan may involve activation of B-[[MYB]]. 
|mesh-terms=* Aging
* Animals
* Cell Cycle Checkpoints
* Cell Proliferation
* Cellular Senescence
* Humans
* Proto-Oncogene Proteins c-myb
* Signal Transduction
|keywords=* B-MYB
* MuvB
* aging
* cellular senescence
* growth arrest
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331756
}}
{{medline-entry
|title=MiR-506 suppresses proliferation and induces senescence by directly targeting the [[CDK4]]/6-[[FOXM1]] axis in ovarian cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24604117
|abstract=Ovarian carcinoma is the most lethal gynaecological malignancy. Better understanding of the molecular pathogenesis of this disease and effective targeted therapies are needed to improve patient outcomes. MicroRNAs play important roles in cancer progression and have the potential for use as either therapeutic agents or targets. Studies in other cancers have suggested that miR-506 has anti-tumour activity, but its function has yet to be elucidated. We found that deregulation of miR-506 in ovarian carcinoma promotes an aggressive phenotype. Ectopic over-expression of miR-506 in ovarian cancer cells was sufficient to inhibit proliferation and to promote senescence. We also demonstrated that [[CDK4]] and [[CDK6]] are direct targets of miR-506, and that miR-506 can inhibit [[CDK4]]/6-[[FOXM1]] signalling, which is activated in the majority of serous ovarian carcinomas. This newly recognized miR-506-[[CDK4]]/6-[[FOXM1]] axis provides further insight into the pathogenesis of ovarian carcinoma and identifies a potential novel therapeutic agent.
|mesh-terms=* 3' Untranslated Regions
* Binding Sites
* Cell Line, Tumor
* Cell Proliferation
* Cell Survival
* Cellular Senescence
* Cyclin-Dependent Kinase 4
* Cyclin-Dependent Kinase 6
* Female
* Forkhead Box Protein M1
* Forkhead Transcription Factors
* Gene Expression Regulation, Neoplastic
* Genotype
* Humans
* MicroRNAs
* Neoplasms, Cystic, Mucinous, and Serous
* Ovarian Neoplasms
* Phenotype
* Signal Transduction
* Time Factors
* Transfection
|keywords=* FOXM1
* miR-506
* ovarian carcinoma
* proliferation
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144705
}}