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2 results on '"CDKN1A, cyclin-dependent kinase inhibitor 1A"'

1. Wnt-induced, TRP53-mediated Cell Cycle Arrest of Precursors Underlies Interstitial Cell of Cajal Depletion During AgingSummary

Author

Huihuang Yan, Khashayarsha Khazaie, Gianrico Farrugia, Sabriya A. Syed, Michelle Wehling-Henricks, Makoto Kuro-o, Simon J. Gibbons, Sergiy M. Kvasha, David T. Asuzu, Rea A. Nagy, Eduardo N. Chini, Mahendra Pal Singh, Yujiro Hayashi, David R. Linden, James G. Tidball, Gabriella B. Gajdos, Michael R. Bardsley, Jair Machado Espindola Netto, Siva Arumugam Saravanaperumal, Todd A. Kellogg, Tamas Ordog, and Yoshitaka Toyomasu

Subjects
PE, R-phycoerythrin, Male, 0301 basic medicine, CL.CASP3, cleaved caspase 3, Aging, Cell cycle checkpoint, BrdU, 5-bromo-2′-deoxyuridine, DMSO, dimethyl sulfoxide, Mice, 0302 clinical medicine, APC, allophycocyanin, ERK, extracellular signal-regulated kinase, GSEA, gene set enrichment analysis, GEO, Gene Expression Omnibus, NES, normalized enrichment score, TRP53, transformation related protein 53, Wnt Signaling Pathway, Klotho, ANOVA, analysis of variance, Cellular Senescence, Original Research, SA-β-gal, senescence-associated beta-galactosidase, KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog, Stomach, EdU, 5-ethynyl-2′-deoxyuridine, Gastroenterology, Wnt signaling pathway, MTS, methyltetrazolium salt, ICC, interstitial cells of Cajal, Middle Aged, CDKN1A, cyclin-dependent kinase inhibitor 1a, Up-Regulation, Cell biology, CTNNB1, catenin beta 1, GAPDH, glyceraldehyde-3-phosphate dehydrogenase, Models, Animal, symbols, Female, 030211 gastroenterology & hepatology, ANO1, anoctamin-1, RPKM, reads per kilobase of transcript per million mapped reads, Stem cell, Compliance, Senescence, SESN, sestrin, tsTAg, tsA58-mutant SV40 large T antigen, Adenomatous Polyposis Coli Protein, FDR Q, false discovery rate Q value, Mice, Transgenic, KLF4, Kruppel-like factor 4, Biology, DDR, DNA damage response, PI, propidium iodide, Young Adult, 03 medical and health sciences, symbols.namesake, Cyclin D1, RT-qPCR, real-time quantitative reverse-transcription polymerase chain reaction, Stem Cell, MEK, mitogen-activated protein kinase kinase, Animals, Humans, Kinase activity, lcsh:RC799-869, Klotho Proteins, CCND1, cyclin D1, Hepatology, WB, Western immunoblotting, RNA-seq, RNA sequencing, Cell Cycle Checkpoints, Interstitial Cells of Cajal, CDKN1B, cyclin-dependent kinase inhibitor 2B, WT, wild-type, Interstitial cell of Cajal, 030104 developmental biology, siRNA, small interfering RNA, ETV1, ets variant 1, ICC-SC, interstitial cells of Cajal stem cells, lcsh:Diseases of the digestive system. Gastroenterology, Tumor Suppressor Protein p53, MYC, myelocytomatosis oncogene, DAPI, 4′,6-diamidino-2-phenylindole
Abstract

Background & Aims Gastric dysfunction in the elderly may cause reduced food intake, frailty, and increased mortality. The pacemaker and neuromodulator cells interstitial cells of Cajal (ICC) decline with age in humans, and their loss contributes to gastric dysfunction in progeric klotho mice hypomorphic for the anti-aging Klotho protein. The mechanisms of ICC depletion remain unclear. Klotho attenuates Wnt (wingless-type MMTV integration site) signaling. Here, we examined whether unopposed Wnt signaling could underlie aging-associated ICC loss by up-regulating transformation related protein TRP53 in ICC stem cells (ICC-SC). Methods Mice aged 1–107 weeks, klotho mice, APCΔ468 mice with overactive Wnt signaling, mouse ICC-SC, and human gastric smooth muscles were studied by RNA sequencing, reverse transcription–polymerase chain reaction, immunoblots, immunofluorescence, histochemistry, flow cytometry, and methyltetrazolium, ethynyl/bromodeoxyuridine incorporation, and ex-vivo gastric compliance assays. Cells were manipulated pharmacologically and by gene overexpression and RNA interference. Results The klotho and aged mice showed similar ICC loss and impaired gastric compliance. ICC-SC decline preceded ICC depletion. Canonical Wnt signaling and TRP53 increased in gastric muscles of klotho and aged mice and middle-aged humans. Overstimulated canonical Wnt signaling increased DNA damage response and TRP53 and reduced ICC-SC self-renewal and gastric ICC. TRP53 induction persistently inhibited G1/S and G2/M cell cycle phase transitions without activating apoptosis, autophagy, cellular quiescence, or canonical markers/mediators of senescence. G1/S block reflected increased cyclin-dependent kinase inhibitor 1B and reduced cyclin D1 from reduced extracellular signal-regulated kinase activity. Conclusions Increased Wnt signaling causes age-related ICC loss by up-regulating TRP53, which induces persistent ICC-SC cell cycle arrest without up-regulating canonical senescence markers., Graphical abstract

Published
2021

2. Decreased osteoprogenitor proliferation precedes attenuation of cancellous bone formation in ovariectomized rats treated with sclerostin antibody

Author

Rogely W. Boyce, Kathrin Locher, Scott Taylor, Ian Pyrah, Nacera Mellal, Danielle L. Brown, Michael S. Ominsky, and Melanie Felx

Subjects
0301 basic medicine, Cell signaling, lcsh:Diseases of the musculoskeletal system, Endocrinology, Diabetes and Metabolism, Osteoporosis, BrdU, 5-bromo-2′-deoxyuridine, SURS, systematic uniform random sampling, TP53, tumor protein p53, CDKN1A, cyclin-dependent kinase inhibitor 1A, CE, coefficient of error, OP, osteoprogenitor(s), OCy, osteocyte(s), chemistry.chemical_compound, 0302 clinical medicine, RB1, retinoblastoma protein 1, PROBE, precision range of an optimally balanced estimator, Scl-Ab, sclerostin antibody, Orthopedics and Sports Medicine, OVX, ovariectomized, ANOVA, analysis of variance, Chemistry, MYC, v-myc avian myelocytomatosis viral oncogene homolog, Ob.N, OB number, Wnt signaling pathway, medicine.anatomical_structure, FOXM1, Forkhead box protein M1, Osteocyte, Ovariectomized rat, Signal transduction, Cancellous bone, CDKN2A, CDKN inhibitor 2A, medicine.medical_specialty, Osteoprogenitors, 030209 endocrinology & metabolism, Article, 03 medical and health sciences, Scl-AbVI, 50 mg/kg of a Scl-Ab, Internal medicine, medicine, Bone, E2F1, E2F transcription factor 1, OB, osteoblast(s), Anabolics, CV, coefficient of variation, medicine.disease, Wnt signaling, VEH, vehicle, D, day, 030104 developmental biology, Endocrinology, MS/BS, mineralizing surface per bone surface, Sclerostin, RUNX2, Runt-related transcription factor 2, MYCN, MYC neuroblastoma-derived homolog, lcsh:RC925-935
Abstract

Sclerostin antibody (Scl-Ab) stimulates bone formation, which with long-term treatment, attenuates over time. The cellular and molecular mechanisms responsible for the attenuation of bone formation are not well understood, but in aged ovariectomized (OVX) rats, the reduction in vertebral cancellous bone formation is preceded by a reduction in osteoprogenitor (OP) number and significant induction of signaling pathways known to suppress mitogenesis and cell cycle progression in the osteocyte (OCy) (Taylor et al., 2016). To determine if the reduction in OP number is associated with a decrease in proliferation, aged OVX rats were administered vehicle or Scl-Ab for 9 or 29 days and implanted with continuous-delivery 5-bromo-2′-deoxyuridine (BrdU) mini-osmotic pumps 5 days prior to necropsy. The total number of BrdU-labeled osteoblasts (OB) was quantified in vertebral cancellous bone to indirectly assess the effects of Scl-Ab treatment on OP proliferation at the time of activation of modeling-based bone formation at day 9 and at the time of maximal mineralizing surface, initial decrease in OP number, and transcriptional changes in the OCy at day 29. Compared with vehicle, Scl-Ab resulted in an increase in the total number of BrdU-positive OB (+260%) at day 9 that decreased with continued treatment (+50%) at day 29. These differences in proliferation occurred at time points when the increase in total OB number was significant and similar in magnitude. These findings suggest that reduced OP proliferation contributes to the decrease in OP numbers, an effect that would limit the OB pool and contribute to the attenuation of bone formation that occurs with long-term Scl-Ab treatment., Highlights • Sclerostin antibody stimulates bone formation (BF) that attenuates over time. • Osteoprogenitor (OP) proliferation increases early with treatment. • Attenuation of BF is preceded by a decrease in OP proliferation. • Decrease is coincident with molecular signaling consistent with cell cycle arrest. • Decreased OP proliferation contributes to the attenuation of BF.

Published
2018
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