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Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers.
Song W, Hwang Y, Youngblood VM, Cook RS, Balko JM, Chen J, Brantley-Sieders DM
(2017) Oncogene 36: 5620-5630
MeSH Terms: Animals, Benzamides, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p27, Ephrin-A2, Female, Gene Knockdown Techniques, Humans, Mice, Mice, Inbred NOD, Mice, Nude, Mice, SCID, Neoplasm Recurrence, Local, Niacinamide, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-myb, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays
Show Abstract · Added March 14, 2018
Basal-like/triple-negative breast cancers (TNBCs) are among the most aggressive forms of breast cancer, and disproportionally affects young premenopausal women and women of African descent. Patients with TNBC suffer a poor prognosis due in part to a lack of molecularly targeted therapies, which represents a critical barrier for effective treatment. Here, we identify EphA2 receptor tyrosine kinase as a clinically relevant target for TNBC. EphA2 expression is enriched in the basal-like molecular subtype in human breast cancers. Loss of EphA2 function in both human and genetically engineered mouse models of TNBC reduced tumor growth in culture and in vivo. Mechanistically, targeting EphA2 impaired cell cycle progression through S-phase via downregulation of c-Myc and stabilization of the cyclin-dependent kinase inhibitor p27/KIP1. A small molecule kinase inhibitor of EphA2 effectively suppressed tumor cell growth in vivo, including TNBC patient-derived xenografts. Thus, our data identify EphA2 as a novel molecular target for TNBC.
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20 MeSH Terms
Phosphatidylinositol 3-kinase signaling determines kidney size.
Chen JK, Nagai K, Chen J, Plieth D, Hino M, Xu J, Sha F, Ikizler TA, Quarles CC, Threadgill DW, Neilson EG, Harris RC
(2015) J Clin Invest 125: 2429-44
MeSH Terms: Animals, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Immunosuppressive Agents, Kidney, Kidney Diseases, Mechanistic Target of Rapamycin Complex 2, Mice, Mice, Inbred DBA, Mice, Knockout, Multiprotein Complexes, Organ Size, Phosphatidylinositol 3-Kinases, Phosphorylation, Proto-Oncogene Proteins c-akt, Ribosomal Protein S6 Kinases, 90-kDa, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases
Show Abstract · Added August 5, 2015
Kidney size adaptively increases as mammals grow and in response to the loss of 1 kidney. It is not clear how kidneys size themselves or if the processes that adapt kidney mass to lean body mass also mediate renal hypertrophy following unilateral nephrectomy (UNX). Here, we demonstrated that mice harboring a proximal tubule-specific deletion of Pten (Pten(ptKO)) have greatly enlarged kidneys as the result of persistent activation of the class I PI3K/mTORC2/AKT pathway and an increase of the antiproliferative signals p21(Cip1/WAF) and p27(Kip1). Administration of rapamycin to Pten(ptKO) mice diminished hypertrophy. Proximal tubule-specific deletion of Egfr in Pten(ptKO) mice also attenuated class I PI3K/mTORC2/AKT signaling and reduced the size of enlarged kidneys. In Pten(ptKO) mice, UNX further increased mTORC1 activation and hypertrophy in the remaining kidney; however, mTORC2-dependent AKT phosphorylation did not increase further in the remaining kidney of Pten(ptKO) mice, nor was it induced in the remaining kidney of WT mice. After UNX, renal blood flow and amino acid delivery to the remaining kidney rose abruptly, followed by increased amino acid content and activation of a class III PI3K/mTORC1/S6K1 pathway. Thus, our findings demonstrate context-dependent roles for EGFR-modulated class I PI3K/mTORC2/AKT signaling in the normal adaptation of kidney size and PTEN-independent, nutrient-dependent class III PI3K/mTORC1/S6K1 signaling in the compensatory enlargement of the remaining kidney following UNX.
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19 MeSH Terms
Deletion of ErbB4 accelerates polycystic kidney disease progression in cpk mice.
Zeng F, Miyazawa T, Kloepfer LA, Harris RC
(2014) Kidney Int 86: 538-47
MeSH Terms: Animals, Apoptosis, Blood Urea Nitrogen, Caspase 3, Cell Proliferation, Cyclin D, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Disease Models, Animal, Disease Progression, Epithelial Cells, Fibrosis, Gene Deletion, Kidney Cortex, Kidney Medulla, Mice, Organ Size, Polycystic Kidney Diseases, Receptor, ErbB-4
Show Abstract · Added October 27, 2014
ErbB4 is highly expressed in the cystic kidneys with polycystic kidney diseases. To investigate its potential role in cystogenesis, cpk mice carrying a heart-rescued ErbB4 deletion were generated. Accelerated cyst progression and renal function deterioration were noted as early as 10 days postnatally in cpk mice with ErbB4 deletion compared to cpk mice, as indicated by increased cystic index, higher kidney weight to body weight ratios, and elevated BUN levels. No apparent defects in renal development were noted with ErbB4 deletion itself. Increased cell proliferation was predominately seen in the cortex of cystic kidneys with or without ErbB4 deletion. However, there was significantly more cell proliferation in the cyst-lining epithelial cells in cpk mice with ErbB4 deletion. TUNEL staining localized apoptotic cells mainly to the renal medulla. There were significantly more apoptotic cells in the cyst-lining epithelial cells in ErbB4-deleted cpk kidneys, with decreased levels of cyclin D1, increased levels of p21, p27, and cleaved caspase 3. Thus, lack of ErbB4 may contribute to elevated cell proliferation and unbalanced cell apoptosis, resulting in accelerated cyst formation and early renal function deterioration. These studies suggest that the high level of ErbB4 expression seen in cpk mice may exert relative cytoprotective effects in renal epithelia.
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19 MeSH Terms
Differential regulation of cyclin-dependent kinase inhibitors in neuroblastoma cells.
Qiao L, Paul P, Lee S, Qiao J, Wang Y, Chung DH
(2013) Biochem Biophys Res Commun 435: 295-9
MeSH Terms: Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Gastrin-Releasing Peptide, Gene Expression Regulation, Neoplastic, Humans, Neuroblastoma, PTEN Phosphohydrolase, Receptors, Bombesin
Show Abstract · Added March 7, 2014
Gastrin-releasing peptide (GRP) and its receptor (GRP-R) are highly expressed in undifferentiated neuroblastoma, and they play critical roles in oncogenesis. We previously reported that GRP activates the PI3K/AKT signaling pathway to promote DNA synthesis and cell cycle progression in neuroblastoma cells. Conversely, GRP-R silencing induces cell cycle arrest. Here, we speculated that GRP/GRP-R signaling induces neuroblastoma cell proliferation via regulation of cyclin-dependent kinase (CDK) inhibitors. Surprisingly, we found that GRP/GRP-R differentially induced expressions of p21 and p27. Silencing GRP/GRP-R decreased p21, but it increased p27 expressions in neuroblastoma cells. Furthermore, we found that the intracellular localization of p21 and p27 in the nuclear and cytoplasmic compartments, respectively. In addition, we found that GRP/GRP-R silencing increased the expression and accumulation of PTEN in the cytoplasm of neuroblastoma cells where it co-localized with p27, thus suggesting that p27 promotes the function of PTEN as a tumor suppressor by stabilizing PTEN in the cytoplasm. GRP/GRP-R regulation of CDK inhibitors and tumor suppressor PTEN may be critical for tumoriogenesis of neuroblastoma.
Copyright © 2013 Elsevier Inc. All rights reserved.
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9 MeSH Terms
Vsx2 controls eye organogenesis and retinal progenitor identity via homeodomain and non-homeodomain residues required for high affinity DNA binding.
Zou C, Levine EM
(2012) PLoS Genet 8: e1002924
MeSH Terms: Alleles, Animals, Cyclin-Dependent Kinase Inhibitor p27, DNA-Binding Proteins, Eye, Gene Expression Regulation, Developmental, HEK293 Cells, Homeodomain Proteins, Humans, Mice, Mice, Transgenic, Microphthalmia-Associated Transcription Factor, Mutation, Organogenesis, Otx Transcription Factors, Protein Structure, Tertiary, Retina, Transcription Factors
Show Abstract · Added November 2, 2015
The homeodomain and adjacent CVC domain in the visual system homeobox (VSX) proteins are conserved from nematodes to humans. Humans with missense mutations in these regions of VSX2 have microphthalmia, suggesting both regions are critical for function. To assess this, we generated the corresponding mutations in mouse Vsx2. The homeodomain mutant protein lacked DNA binding activity and the knock-in mutant phenocopied the null mutant, ocular retardation J. The CVC mutant protein exhibited weakened DNA binding; and, although the corresponding knock-in allele was recessive, it unexpectedly caused the strongest phenotype, as indicated by severe microphthalmia and hyperpigmentation of the neural retina. This occurred through a cryptic transcriptional feedback loop involving the transcription factors Mitf and Otx1 and the Cdk inhibitor p27(Kip1). Our data suggest that the phenotypic severity of the CVC mutant depends on the weakened DNA binding activity elicited by the CVC mutation and a previously unknown protein interaction between Vsx2 and its regulatory target Mitf. Our data also suggest that an essential function of the CVC domain is to assist the homeodomain in high-affinity DNA binding, which is required for eye organogenesis and unhindered execution of the retinal progenitor program in mammals. Finally, the genetic and phenotypic behaviors of the CVC mutation suggest it has the characteristics of a recessive neomorph, a rare type of genetic allele.
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18 MeSH Terms
Association of genetic polymorphisms in cell-cycle control genes and susceptibility to endometrial cancer among Chinese women.
Cai H, Xiang YB, Qu S, Long J, Cai Q, Gao J, Zheng W, Shu XO
(2011) Am J Epidemiol 173: 1263-71
MeSH Terms: Adult, Aged, Body Mass Index, Case-Control Studies, China, Cyclin-Dependent Kinase Inhibitor p27, Endometrial Neoplasms, Female, Genes, cdc, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Health Behavior, Humans, Middle Aged, Polymorphism, Single Nucleotide, Socioeconomic Factors
Show Abstract · Added December 10, 2013
Although genetic variations in cell-cycle control genes have been previously linked to cancer risk, no study has specifically evaluated the role of these gene variants in endometrial carcinogenesis. Using data from the Shanghai Endometrial Cancer Study, a population-based case-control study with 1,199 cases and 1,212 age-matched controls (1997-2003), the authors carried out a systematic evaluation of the association of cell-cycle control genes with endometrial cancer risk. Sixty-five tagging or potentially functional single nucleotide polymorphisms in the CCNB1, CCND1, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, and CDKN2A genes were genotyped and evaluated. Three single nucleotide polymorphisms in the CDKN1B gene (rs11055027, rs3759216, and rs34330) were related to endometrial cancer risk, although only the association with rs34330 remained statistically significant after adjustment for multiple comparisons. The odds ratios for rs34330 were 1.33 (95% confidence interval (CI): 1.06, 1.66) and 1.51 (95% CI: 1.16, 1.94) for the CT and TT genotypes, respectively, compared with the CC genotype. In vitro luciferase reporter assays showed that the minor allele (A) in rs3759216, which was associated with decreased endometrial cancer risk (odds ratio = 0.73, 95% CI: 0.56, 0.94) without adjustment for multiple comparisons, significantly increased promoter activity. These findings suggest that polymorphisms of the CDKN1B gene may play a role in endometrial carcinogenesis.
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17 MeSH Terms
Renal oxygenation suppresses VHL loss-induced senescence that is caused by increased sensitivity to oxidative stress.
Welford SM, Dorie MJ, Li X, Haase VH, Giaccia AJ
(2010) Mol Cell Biol 30: 4595-603
MeSH Terms: Animals, Blotting, Western, Cell Proliferation, Cells, Cultured, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p27, DNA Damage, Embryo, Mammalian, Epithelial Cells, Fibroblasts, Herbicides, Kidney, Kidney Tubules, Mice, Mice, Knockout, Oxidative Stress, Oxygen, Paraquat, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Protein p53, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added August 19, 2013
Loss of the VHL tumor suppressor is regarded as an initiating event in the development of clear-cell renal carcinoma. Surprisingly, loss of VHL induces senescence in mouse fibroblasts in vitro, a response that would restrict development of renal carcinoma in vivo. Typical in vitro cell culture levels of oxygen, however, are significantly higher than physiological levels of oxygen, which have been shown to abrogate senescence induced by many stimuli. Therefore, we investigated the oxygen dependence of VHL loss-induced senescence. Using mouse fibroblasts and primary renal epithelial cells in vitro, we found that VHL loss leads to senescence under atmospheric conditions (21% O(2)), partly through increasing p27 levels, but not under physiological oxygenation (2% to 5% O(2)), despite maintaining increased p27 expression. This suggests that VHL inactivation sensitizes cells to oxidative stress. In support of this concept, senescence following VHL loss depends on p53 activity, which decreases under the less stressful conditions of mild hypoxia. We confirmed these observations in vivo by treating kidney-specific VHL knockout animals with the potent oxidizer paraquat and observed a robust induction of cellular senescence. Together, these data demonstrate that in vivo oxygenation promotes tolerance of VHL loss in renal epithelia, which may promote the development of renal carcinoma.
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22 MeSH Terms
RSK1 drives p27Kip1 phosphorylation at T198 to promote RhoA inhibition and increase cell motility.
Larrea MD, Hong F, Wander SA, da Silva TG, Helfman D, Lannigan D, Smith JA, Slingerland JM
(2009) Proc Natl Acad Sci U S A 106: 9268-73
MeSH Terms: Actins, Cell Line, Tumor, Cell Movement, Cyclin-Dependent Kinase Inhibitor p27, Cytoplasm, G1 Phase, Humans, Intracellular Signaling Peptides and Proteins, MAP Kinase Signaling System, Phosphorylation, Ribosomal Protein S6 Kinases, 90-kDa, Signal Transduction, rhoA GTP-Binding Protein
Show Abstract · Added January 20, 2015
p90 ribosomal S6 kinase (RSK1) is an effector of both Ras/MEK/MAPK and PI3K/PDK1 pathways. We present evidence that RSK1 drives p27 phosphorylation at T198 to increase RhoA-p27 binding and cell motility. RSK1 activation and p27pT198 both increase in early G(1). As for many kinase-substrate pairs, cellular RSK1 coprecipitates with p27. siRNA to RSK1 and RSK1 inhibition both rapidly reduce cellular p27pT198. RSK1 overexpression increases p27pT198, p27-cyclin D1-Cdk4 complexes, and p27 stability. Moreover, RSK1 transfectants show mislocalization of p27 to cytoplasm, increased motility, and reduced RhoA-GTP, phospho-cofilin, and actin stress fibers, all of which were reversed by shRNA to p27. Phosphorylation by RSK1 increased p27pT198 binding to RhoA in vitro, whereas p27T157A/T198A bound poorly to RhoA compared with WTp27 in cells. Coprecipitation of cellular p27-RhoA was increased in cells with constitutive PI3K activation and increased in early G(1). Thus T198 phosphorylation not only stabilizes p27 and mislocalizes p27 to the cytoplasm but also promotes RhoA-p27 interaction and RhoA pathway inhibition. These data link p27 phosphorylation at T198 and cell motility. As for other PI3K effectors, RSK1 phosphorylates p27 at T198. Because RSK1 is also activated by MAPK, the increased cell motility and metastatic potential of cancer cells with PI3K and/or MAPK pathway activation may result in part from RSK1 activation, leading to accumulation of p27T198 in the cytoplasm, p27:RhoA binding, inhibition of RhoA/Rock pathway activation, and loss of actomyosin stability.
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13 MeSH Terms
Cyclin D1 fine-tunes the neurogenic output of embryonic retinal progenitor cells.
Das G, Choi Y, Sicinski P, Levine EM
(2009) Neural Dev 4: 15
MeSH Terms: Animals, Animals, Newborn, Bromodeoxyuridine, Cell Cycle, Cyclin D1, Cyclin-Dependent Kinase Inhibitor p27, Embryo, Mammalian, Embryonic Stem Cells, Gene Expression Regulation, Developmental, Homeodomain Proteins, Humans, Mice, Mice, Knockout, Neurogenesis, Neurons, Otx Transcription Factors, Proliferating Cell Nuclear Antigen, Retina, Thymidine, Transcription Factor Brn-3B, Tubulin
Show Abstract · Added November 2, 2015
BACKGROUND - Maintaining the correct balance of proliferation versus differentiation in retinal progenitor cells (RPCs) is essential for proper development of the retina. The cell cycle regulator cyclin D1 is expressed in RPCs, and mice with a targeted null allele at the cyclin D1 locus (Ccnd1-/-) have microphthalmia and hypocellular retinas, the latter phenotype attributed to reduced RPC proliferation and increased photoreceptor cell death during the postnatal period. How cyclin D1 influences RPC behavior, especially during the embryonic period, is unclear.
RESULTS - In this study, we show that embryonic RPCs lacking cyclin D1 progress through the cell cycle at a slower rate and exit the cell cycle at a faster rate. Consistent with enhanced cell cycle exit, the relative proportions of cell types born in the embryonic period, such as retinal ganglion cells and photoreceptor cells, are increased. Unexpectedly, cyclin D1 deficiency decreases the proportions of other early born retinal neurons, namely horizontal cells and specific amacrine cell types. We also found that the laminar positioning of horizontal cells and other cell types is altered in the absence of cyclin D1. Genetically replacing cyclin D1 with cyclin D2 is not efficient at correcting the phenotypes due to the cyclin D1 deficiency, which suggests the D-cyclins are not fully redundant. Replacement with cyclin E or inactivation of cyclin-dependent kinase inhibitor p27Kip1 restores the balance of RPCs and retinal cell types to more normal distributions, which suggests that regulation of the retinoblastoma pathway is an important function for cyclin D1 during embryonic retinal development.
CONCLUSION - Our findings show that cyclin D1 has important roles in RPC cell cycle regulation and retinal histogenesis. The reduction in the RPC population due to a longer cell cycle time and to an enhanced rate of cell cycle exit are likely to be the primary factors driving retinal hypocellularity and altered output of precursor populations in the embryonic Ccnd1-/- retina.
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21 MeSH Terms
Distinct roles for p107 and p130 in Rb-independent cellular senescence.
Lehmann BD, Brooks AM, Paine MS, Chappell WH, McCubrey JA, Terrian DM
(2008) Cell Cycle 7: 1262-8
MeSH Terms: Carcinoma, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Cellular Senescence, Crk-Associated Substrate Protein, Cyclin-Dependent Kinase Inhibitor p27, DNA Damage, Down-Regulation, Genes, cdc, Humans, Male, Prostatic Neoplasms, Radiation, Retinoblastoma Protein, Retinoblastoma-Like Protein p107, Tumor Suppressor Proteins
Show Abstract · Added January 20, 2015
Telomere attrition, DNA damage and constitutive mitogenic signaling can all trigger cellular senescence in normal cells and serve as a defense against tumor progression. Cancer cells may circumvent this cellular defense by acquiring genetic mutations in checkpoint proteins responsible for regulating permanent cell cycle arrest. A small family of tumor suppressor genes encoding the retinoblastoma susceptibility protein family (Rb, p107, p130) exerts a partially redundant control of entry into S phase of DNA replication and cellular proliferation. Here we report that activation of the p53-dependent DNA damage response has been found to accelerate senescence in human prostate cancer cells lacking a functional Rb protein. This novel form of irradiation-induced premature cellular senescence reinforces the notion that other Rb family members may compensate for loss of Rb protein in the DNA damage response pathway. Consistent with this hypothesis, depletion of p107 potently inhibits the irradiation-induced senescence observed in DU145 cells. In contrast, p130 depletion triggers a robust and unexpected form of premature senescence in unirradiated cells. The dominant effect of depleting both p107 and p130, in the absence of Rb, was a complete blockade of irradiation-induced cellular senescence. Onset of the p107-dependent senescence was temporally associated with p53-mediated stabilization of the cyclin-dependent kinase inhibitor p27 and decreases in c-myc and cks1 expression. These results indicate that p107 is required for initiation of accelerated cellular senescence in the absence of Rb and introduces the concept that p130 may be required to prevent the onset of terminal growth arrest in unstimulated prostate cancer cells lacking a functional Rb allele.
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17 MeSH Terms