Редактирование: RB1 (раздел)

==Publications==

{{medline-entry
|title=Expression of p16 in nodular fasciitis: an implication for self-limited and inflammatory nature of the lesion.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31933915
|abstract=Nodular fasciitis (NF) is a self-limited tumorous lesion occurring in the upper as well as lower extremities. NF is composed of a proliferation of "primary culture"-like myofibroblastic cells with nuclear atypia and large nucleoli, thus mimicking sarcoma. NF harbors a promoter-swapping fusion gene containing the entire coding region of [i]USP6[/i] gene. Therefore, NF is a tumor with a fusion oncogene but self-limited. In order to explore why NF is self-limited, we examined whether myofibroblastic cells in NF express p16 protein, a gene product of [i]CDKN2A[/i] gene and an inhibitor of cyclin-dependent kinase 4 ([[CDK4]]) as well as one of the hallmarks of cellular senescence. We immunohistochemically demonstrated strong and diffuse expression of p16 in myofibroblastic cells in 11 out of 15 cases of NF, and strong but partial expression in the remaining 4 of the cases. We also showed that 15 out of 15 cases of NF were immunohistochemically negative or only showed focal and faint immunopositivity for [[CDK4]], murine double minute 2 (MDM2), and [[TP53]] proteins. Furthermore, there were no significant changes in the copy number of [i]CDKN2A, [[CDK4]][/i] and [i]MDM2[/i] genes, and no significant mutations in [i][[TP53]], [[RB1]],[/i] and [i]CDKN2A[/i] genes in 1 case of NF selected. These data suggest a possible involvement in cell cycle arrest and presumed cellular senescence by p16 in myofibroblastic cells in NF. This may explain the self-limited as well as inflammatory nature of NF as a senescence-associated secretory phenotype.

|keywords=* CDK4
* MDM2
* TP53
* nodular fasciitis
* p16
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945175
}}
{{medline-entry
|title=G protein-coupled receptor kinase 4-induced cellular senescence and its senescence-associated gene expression profiling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28912086
|abstract=Senescent cells have lost their capacity for proliferation and manifest as irreversibly in cell cycle arrest. Many membrane receptors, including G protein-coupled receptors (GPCRs), initiate a variety of intracellular signaling cascades modulating cell division and potentially play roles in triggering cellular senescence response. GPCR kinases (GRKs) belong to a family of serine/threonine kinases. Although their role in homologous desensitization of activated GPCRs is well established, the involvement of the kinases in cell proliferation is still largely unknown. In this study, we isolated [[GRK4]]-GFP expressing HEK293 cells by fluorescence-activated cell sorting (FACS) and found that the ectopic expression of [[GRK4]] halted cell proliferation. Cells expressing [[GRK4]] ([[GRK4]]( )) demonstrated cell cycle G1/G0 phase arrest, accompanied with significant increase of senescence-associated-β-galactosidase (SA-β-Gal) activity. Expression profiling analysis of 78 senescence-related genes by qRT-PCR showed a total of 17 genes significantly changed in [[GRK4]]( ) cells (≥ 2 fold, p < 0.05). Among these, 9 genes - [[AKT1]], p16 , p27 , p19 , [[IGFBP3]], [[MAPK14]], [[PLAU]], [[THBS1]], [[TP73]] - were up-regulated, while 8 genes, Cyclin A2, Cyclin D1, [[CDK2]], [[CDK6]], [[ETS1]], [[NBN]], [[RB1]], [[SIRT1]], were down-regulated. The increase in cyclin-dependent kinase inhibitors (p16, p27) and p38 MAPK proteins ([[MAPK14]]) was validated by immunoblotting. Neither p53 nor p21  protein was detectable, suggesting no p53 activation in the HEK293 cells. These results unveil a novel function of [[GRK4]] on triggering a p53-independent cellular senescence, which involves an intricate signaling network.
|mesh-terms=* Cell Division
* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* Flow Cytometry
* G-Protein-Coupled Receptor Kinase 4
* Gene Expression Profiling
* Gene Expression Regulation
* HEK293 Cells
* Humans
* MCF-7 Cells
* Transcriptome
* Tumor Suppressor Protein p53
|keywords=* Cellular senescence
* G protein-coupled receptor kinase 4
* Gene expression profiling
* p53-independent senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944352
}}
{{medline-entry
|title=Mesenchymal stromal cells having inactivated [[RB1]] survive following low irradiation and accumulate damaged DNA: Hints for side effects following radiotherapy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27124644
|abstract=Following radiotherapy, bone sarcomas account for a significant percentage of recurring tumors. This risk is further increased in patients with hereditary retinoblastoma that undergo radiotherapy. We analyzed the effect of low and medium dose radiation on mesenchymal stromal cells ([[MSC]]s) with inactivated [[RB1]] gene to gain insights on the molecular mechanisms that can induce second malignant neoplasm in cancer survivors. [[MSC]] cultures contain subpopulations of mesenchymal stem cells and committed progenitors that can differentiate into mesodermal derivatives: adipocytes, chondrocytes, and osteocytes. These stem cells and committed osteoblast precursors are the cell of origin in osteosarcoma, and [[RB1]] gene mutations have a strong role in its pathogenesis. Following 40 and 2000 mGy X-ray exposure, [[MSC]]s with inactivated [[RB1]] do not proliferate and accumulate high levels of unrepaired DNA as detected by persistence of gamma-[[H2AX]] foci. In samples with inactivated [[RB1]] the radiation treatment did not increase apoptosis, necrosis or senescence versus untreated cells. Following radiation, CFU analysis showed a discrete number of cells with clonogenic capacity in cultures with silenced [[RB1]]. We extended our analysis to the other members of retinoblastoma gene family: RB2/P130 and P107. Also in the [[MSC]]s with silenced RB2/P130 and P107 we detected the presence of cells with unrepaired DNA following X-ray irradiation. Cells with unrepaired DNA may represent a reservoir of cells that may undergo neoplastic transformation. Our study suggests that, following radiotherapy, cancer patients with mutations of retinoblastoma genes may be under strict controls to evaluate onset of secondary neoplasms following radiotherapy.
|mesh-terms=* Apoptosis
* Cell Cycle
* Cell Lineage
* Cell Survival
* Cell Transformation, Neoplastic
* Cellular Senescence
* Colony-Forming Units Assay
* DNA Damage
* DNA Repair
* Gene Silencing
* Histones
* Humans
* Mesenchymal Stem Cells
* Radiotherapy
* Retinoblastoma Protein
* Retinoblastoma-Like Protein p107
* X-Rays
|keywords=* Apoptosis
* DNA damage
* mesenchymal stem cells
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323029
}}
{{medline-entry
|title=Suppression of [[RAD21]] Induces Senescence of MDA-[[MB]]-231 Human Breast Cancer Cells Through [[RB1]] Pathway Activation Via c-Myc Downregulation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26529363
|abstract=Cellular senescence impedes cancer progression by limiting uncontrolled cell proliferation. To identify new genetic events controlling senescence, we performed a small interfering RNA screening human cancer cells and identified a number of targets potentially involved in senescence of MDA-[[MB]]-231 human breast cancer cells. Importantly, we showed that knockdown of [[RAD21]] resulted in the appearance of several senescent markers, including enhanced senescence-associated β-galactosidase activity and heterochromatin focus formation, as well as elevated p21 protein levels and [[RB1]] pathway activation. Further biochemical analyses revealed that [[RAD21]] knockdown led to the downregulation of c-Myc and its targets, including [[CDK4]], a negative regulator of [[RB1]], and blocked[[RB1]] phosphorylation (p[[RB1]]), and the [[RB1]]-mediated transcriptional repression of E2F. Moreover, c-Myc downregulation was partially mediated by proteasome-dependent degradation within promyelocytic leukemia (PML) nuclear bodies, which were found to be highly abundant during [[RAD21]] knockdown-induced senescence. Exogenous c-Myc reconstitution rescued cells from [[RAD21]] silencing-induced senescence. Altogether, data arising from this study implicate a novel function of [[RAD21]] in cellular senescence in MDA-[[MB]]-231 cells that is mainly dependent on[[RB1]] pathway activation via c-Myc downregulation.
|mesh-terms=* Breast Neoplasms
* Cell Cycle Proteins
* Cell Line, Tumor
* Cellular Senescence
* DNA-Binding Proteins
* Down-Regulation
* Female
* Gene Expression Regulation, Neoplastic
* Gene Knockdown Techniques
* Humans
* Nuclear Proteins
* Phosphoproteins
* Proto-Oncogene Proteins c-myc
* RNA, Small Interfering
* Retinoblastoma Binding Proteins
* Signal Transduction
* Ubiquitin-Protein Ligases
|keywords=* MDA-MB-231
* RAD21
* RB1
* SENESCENCE
* c-Myc
|full-text-url=https://sci-hub.do/10.1002/jcb.25426
}}
{{medline-entry
|title=[[RB1]]-mediated cell-autonomous and host-dependent oncosuppressor mechanisms in radiation-induced osteosarcoma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24800165
|abstract=The mechanisms by which retinoblastoma 1 ([[RB1]]) mediates oncosuppressive functions are still being elucidated. We found that radiation-induced senescence in the bone depends on [[RB1]] and is associated with the secretion of multiple bioactive factors, including interleukin-6 (IL-6), as well as with the infiltration of natural killer T (NKT) cells. Importantly, the inhibition of [[RB1]], IL-6 or NKT cells predisposed mice to radiation-induced osteosarcomas, unveiling a cancer cell-extrinsic mechanisms that underlie the oncosuppressive activity of [[RB1]].

|keywords=* interleukin-6
* natural killer T cells
* radiation
* retinoblastoma 1
* senescence
* senescence-associated secretory phenotype (SASP)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006854
}}
{{medline-entry
|title=Drosophila Fip200 is an essential regulator of autophagy that attenuates both growth and aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23819996
|abstract=Autophagy-related 1 (Atg1)/Unc-51-like protein kinases (ULKs) are evolutionarily conserved proteins that play critical physiological roles in controlling autophagy, cell growth and neurodevelopment. [[RB1]]-inducible coiled-coil 1 ([[RB1]]CC1), also known as PTK2/FAK family-interacting protein of 200 kDa (FIP200) is a recently discovered binding partner of [[ULK1]]. Here we isolated the Drosophila [[RB1]]CC1/FIP200 homolog (Fip200/CG1347) and showed that it mediates Atg1-induced autophagy as a genetically downstream component in diverse physiological contexts. Fip200 loss-of-function mutants experienced severe mobility loss associated with neuronal autophagy defects and neurodegeneration. The Fip200 mutants were also devoid of both developmental and starvation-induced autophagy in salivary gland and fat body, while having no defects in axonal transport and projection in developing neurons. Interestingly, moderate downregulation of Fip200 accelerated both developmental growth and aging, accompanied by target of rapamycin (Tor) signaling upregulation. These results suggest that Fip200 is a critical downstream component of Atg1 and specifically mediates Atg1's autophagy-, aging- and growth-regulating functions.
|mesh-terms=* Aging
* Animals
* Autophagy
* Autophagy-Related Protein-1 Homolog
* Axons
* Brain
* Conserved Sequence
* Drosophila Proteins
* Drosophila melanogaster
* Homeostasis
* Motor Activity
* Mutation
* Nerve Degeneration
* Protein-Serine-Threonine Kinases
* Ribosomal Protein S6 Kinases
* Signal Transduction
* TOR Serine-Threonine Kinases
* Time Factors
* Ubiquitin
* Vacuoles
|keywords=* Drosophila
* aging
* autophagy
* growth
* neurodegeneration
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748192
}}