共查询到20条相似文献,搜索用时 31 毫秒
1.
Gwack Y Srikanth S Oh-Hora M Hogan PG Lamperti ED Yamashita M Gelinas C Neems DS Sasaki Y Feske S Prakriya M Rajewsky K Rao A 《Molecular and cellular biology》2008,28(17):5209-5222
ORAI1 is a pore subunit of the store-operated Ca2+ release-activated Ca2+ (CRAC) channel. To examine the physiological consequences of ORAI1 deficiency, we generated mice with targeted disruption of the Orai1 gene. The results of immunohistochemical analysis showed that ORAI1 is expressed in lymphocytes, skin, and muscle of wild-type mice and is not expressed in Orai1−/− mice. Orai1−/− mice with the inbred C57BL/6 background showed perinatal lethality, which was overcome by crossing them to outbred ICR mice. Orai1−/− mice were small in size, with eyelid irritation and sporadic hair loss resembling the cyclical alopecia observed in mice with keratinocyte-specific deletion of the Cnb1 gene. T and B cells developed normally in Orai1−/− mice, but B cells showed a substantial decrease in Ca2+ influx and cell proliferation in response to B-cell receptor stimulation. Naïve and differentiated Orai1−/− T cells showed substantial reductions in store-operated Ca2+ entry, CRAC currents, and cytokine production. These features are consistent with the severe combined immunodeficiency and mild extraimmunological symptoms observed in a patient with a missense mutation in human ORAI1 and distinguish the ORAI1-null mice described here from a previously reported Orai1 gene-trap mutant mouse which may be a hypomorph rather than a true null. 相似文献
2.
p21Waf1/Cip1 Inhibition of Cyclin E/Cdk2 Activity Prevents Endoreduplication after Mitotic Spindle Disruption 总被引:7,自引:0,他引:7
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Zoe A. Stewart Steven D. Leach Jennifer A. Pietenpol 《Molecular and cellular biology》1999,19(1):205-215
During a normal cell cycle, entry into S phase is dependent on completion of mitosis and subsequent activation of cyclin-dependent kinases (Cdks) in G1. These events are monitored by checkpoint pathways. Recent studies and data presented herein show that after treatment with microtubule inhibitors (MTIs), cells deficient in the Cdk inhibitor p21Waf1/Cip1 enter S phase with a ≥4N DNA content, a process known as endoreduplication, which results in polyploidy. To determine how p21 prevents MTI-induced endoreduplication, the G1/S and G2/M checkpoint pathways were examined in two isogenic cell systems: HCT116 p21+/+ and p21−/− cells and H1299 cells containing an inducible p21 expression vector (HIp21). Both HCT116 p21−/− cells and noninduced HIp21 cells endoreduplicated after MTI treatment. Analysis of G1-phase Cdk activities demonstrated that the induction of p21 inhibited endoreduplication through direct cyclin E/Cdk2 regulation. The kinetics of p21 inhibition of cyclin E/Cdk2 activity and binding to proliferating-cell nuclear antigen in HCT116 p21+/+ cells paralleled the onset of endoreduplication in HCT116 p21−/− cells. In contrast, loss of p21 did not lead to deregulated cyclin D1-dependent kinase activities, nor did p21 directly regulate cyclin B1/Cdc2 activity. Furthermore, we show that MTI-induced endoreduplication in p53-deficient HIp21 cells was due to levels of p21 protein below a threshold required for negative regulation of cyclin E/Cdk2, since ectopic expression of p21 restored cyclin E/Cdk2 regulation and prevented endoreduplication. Based on these findings, we propose that p21 plays an integral role in the checkpoint pathways that restrain normal cells from entering S phase after aberrant mitotic exit due to defects in microtubule dynamics. 相似文献
3.
Cyclin-dependent Kinase 2-associating Protein 1 Commits Murine Embryonic Stem Cell Differentiation through Retinoblastoma Protein Regulation 总被引:1,自引:0,他引:1
Yong Kim Amit Deshpande Yanshan Dai Jeffrey J. Kim Anne Lindgren Anne Conway Amander T. Clark David T. Wong 《The Journal of biological chemistry》2009,284(35):23405-23414
4.
Antonio Cerqueira Alberto Martín Catherine E. Symonds Junko Odajima Pierre Dubus Mariano Barbacid David Santamaría 《Molecular and cellular biology》2014,34(8):1452-1459
The Cip/Kip family, namely, p21Cip1, p27Kip1, and p57Kip2, are stoichiometric cyclin-dependent kinase inhibitors (CKIs). Paradoxically, they have been proposed to also act as positive regulators of Cdk4/6-cyclin D by stabilizing these heterodimers. Loss of p21Cip1 and p27Kip1 reduces Cdk4/6-cyclin D complexes, although with limited phenotypic consequences compared to the embryonic lethality of Cdk4/6 or triple cyclin D deficiency. This milder phenotype was attributed to Cdk2 compensatory mechanisms. To address this controversy using a genetic approach, we generated Cdk2−/−
p21−/−
p27−/− mice. Triple-knockout mouse embryonic fibroblasts (MEFs) displayed minimal levels of D-type cyclins and Cdk4/6-cyclin D complexes. p57Kip2 downregulation in the absence of p21Cip1 and p27Kip1 aggravated this phenotype, yet MEFs lacking all Cip/Kip proteins exhibited increased retinoblastoma phosphorylation, together with enhanced proliferation and transformation capacity. In vivo, Cdk2 ablation induced partial perinatal lethality in p21−/−
p27−/− mice, suggesting partial Cdk2-dependent compensation. However, Cdk2−/−
p21−/−
p27−/− survivors displayed all phenotypes described for p27−/− mice, including organomegalia and pituitary tumors. Thus, Cip/Kip deficiency does not impair interphasic Cdk activity even in the absence of Cdk2, suggesting that their Cdk-cyclin assembly function is dispensable for homeostatic control in most cell types. 相似文献
5.
Absence of Macrophage Inflammatory Protein-1α Prevents the Development of Blinding Herpes Stromal Keratitis
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Terrence M. Tumpey Hao Cheng Donald N. Cook Oliver Smithies John E. Oakes Robert N. Lausch 《Journal of virology》1998,72(5):3705-3710
Prior studies in our laboratory have suggested that the CC chemokine macrophage inflammatory protein-1α (MIP-1α) may be an important mediator in the blinding ocular inflammation which develops following herpes simplex virus type 1 (HSV-1) infection of the murine cornea. To directly test this hypothesis, MIP-1α-deficient (−/−) mice and their wild-type (+/+) counterparts were infected topically on the scarified cornea with 2.5 × 105 PFU of HSV-1 strain RE and subsequently graded for corneal opacity. Four weeks postinfection (p.i.), the mean corneal opacity score of −/− mice was 1.1 ± 0.3 while that of the +/+ mice was 3.7 ± 0.5. No detectable infiltrating CD4+ T cells were seen histologically at 14 or 21 days p.i. in −/− animals, whereas the mean CD4+ T-cell count per field (36 fields counted) in +/+ hosts was 26 ± 2 (P < 0.001). In addition, neutrophil counts in the −/− mouse corneas were reduced by >80% in comparison to the wild-type controls. At 2 weeks p.i., no interleukin-2 or gamma interferon could be detected in six of seven −/− mice, whereas both T-cell cytokines were readily demonstrable in +/+ mouse corneas. Also, MIP-2 and monocyte chemoattractant protein-1 protein levels were significantly lower in MIP-1α −/− mouse corneas than in +/+ host corneas, suggesting that MIP-1α directly, or more likely indirectly, influences the expression of other chemokines. Interestingly, despite the paucity of infiltrating cells, HSV-1 clearance from the eyes of −/− mice was not significantly different from that observed in +/+ hosts. We conclude that MIP-1α is not needed to control virus growth in the cornea but is essential for the development of severe stromal keratitis. 相似文献
6.
Cdk2 is critical for proliferation and self-renewal of neural progenitor cells in the adult subventricular zone 总被引:5,自引:0,他引:5
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Jablonska B Aguirre A Vandenbosch R Belachew S Berthet C Kaldis P Gallo V 《The Journal of cell biology》2007,179(6):1231-1245
We investigated the function of cyclin-dependent kinase 2 (Cdk2) in neural progenitor cells during postnatal development. Chondroitin sulfate proteoglycan (NG2)–expressing progenitor cells of the subventricular zone (SVZ) show no significant difference in density and proliferation between Cdk2−/− and wild-type mice at perinatal ages and are reduced only in adult Cdk2−/− mice. Adult Cdk2−/− SVZ cells in culture display decreased self-renewal capacity and enhanced differentiation. Compensatory mechanisms in perinatal Cdk2−/− SVZ cells, which persist until postnatal day 15, involve increased Cdk4 expression that results in retinoblastoma protein inactivation. A subsequent decline in Cdk4 activity to wild-type levels in postnatal day 28 Cdk2−/− cells coincides with lower NG2+ proliferation and self-renewal capacity similar to adult levels. Cdk4 silencing in perinatal Cdk2−/− SVZ cells abolishes Cdk4 up-regulation and reduces cell proliferation and self- renewal to adult levels. Conversely, Cdk4 overexpression in adult SVZ cells restores proliferative capacity to wild-type levels. Thus, although Cdk2 is functionally redundant in perinatal SVZ, it is important for adult progenitor cell proliferation and self-renewal through age-dependent regulation of Cdk4. 相似文献
7.
Katsuya Tanabe Zhonghao Liu Satish Patel Bradley W Doble Lin Li Corentin Cras-Mneur Sara C Martinez Cris M Welling Morris F White Ernesto Bernal-Mizrachi James R Woodgett M. Alan Permutt 《PLoS biology》2008,6(2)
Despite treatment with agents that enhance β-cell function and insulin action, reduction in β-cell mass is relentless in patients with insulin resistance and type 2 diabetes mellitus. Insulin resistance is characterized by impaired signaling through the insulin/insulin receptor/insulin receptor substrate/PI-3K/Akt pathway, leading to elevation of negatively regulated substrates such as glycogen synthase kinase-3β (Gsk-3β). When elevated, this enzyme has antiproliferative and proapoptotic properties. In these studies, we designed experiments to determine the contribution of Gsk-3β to regulation of β-cell mass in two mouse models of insulin resistance. Mice lacking one allele of the insulin receptor (Ir+/−) exhibit insulin resistance and a doubling of β-cell mass. Crossing these mice with those having haploinsufficiency for Gsk-3β (Gsk-3β+/−) reduced insulin resistance by augmenting whole-body glucose disposal, and significantly reduced β-cell mass. In the second model, mice missing two alleles of the insulin receptor substrate 2 (Irs2−/−), like the Ir+/− mice, are insulin resistant, but develop profound β-cell loss, resulting in early diabetes. We found that islets from these mice had a 4-fold elevation of Gsk-3β activity associated with a marked reduction of β-cell proliferation and increased apoptosis. Irs2−/− mice crossed with Gsk-3β+/− mice preserved β-cell mass by reversing the negative effects on proliferation and apoptosis, preventing onset of diabetes. Previous studies had shown that islets of Irs2−/− mice had increased cyclin-dependent kinase inhibitor p27kip1 that was limiting for β-cell replication, and reduced Pdx1 levels associated with increased cell death. Preservation of β-cell mass in Gsk-3β+/−Irs2−/− mice was accompanied by suppressed p27kip1 levels and increased Pdx1 levels. To separate peripheral versus β-cell–specific effects of reduction of Gsk3β activity on preservation of β-cell mass, mice homozygous for a floxed Gsk-3β allele (Gsk-3F/F) were then crossed with rat insulin promoter-Cre (RIP-Cre) mice to produce β-cell–specific knockout of Gsk-3β (βGsk-3β−/−). Like Gsk-3β+/− mice, βGsk-3β−/− mice also prevented the diabetes of the Irs2−/− mice. The results of these studies now define a new, negatively regulated substrate of the insulin signaling pathway specifically within β-cells that when elevated, can impair replication and increase apoptosis, resulting in loss of β-cells and diabetes. These results thus form the rationale for developing agents to inhibit this enzyme in obese insulin-resistant individuals to preserve β-cells and prevent diabetes onset. 相似文献
8.
Seong Gyu Jeon Hisako Kayama Yoshiyasu Ueda Takuya Takahashi Takashi Asahara Hirokazu Tsuji Noriko M. Tsuji Hiroshi Kiyono Ji Su Ma Takashi Kusu Ryu Okumura Hiromitsu Hara Hiroki Yoshida Masahiro Yamamoto Koji Nomoto Kiyoshi Takeda 《PLoS pathogens》2012,8(5)
Specific intestinal microbiota has been shown to induce Foxp3+ regulatory T cell development. However, it remains unclear how development of another regulatory T cell subset, Tr1 cells, is regulated in the intestine. Here, we analyzed the role of two probiotic strains of intestinal bacteria, Lactobacillus casei and Bifidobacterium breve in T cell development in the intestine. B. breve, but not L. casei, induced development of IL-10-producing Tr1 cells that express cMaf, IL-21, and Ahr in the large intestine. Intestinal CD103+ dendritic cells (DCs) mediated B. breve-induced development of IL-10-producing T cells. CD103+ DCs from Il10
−/−, Tlr2
−/−, and Myd88
−/− mice showed defective B. breve-induced Tr1 cell development. B. breve-treated CD103+ DCs failed to induce IL-10 production from co-cultured Il27ra
−/− T cells. B. breve treatment of Tlr2
−/− mice did not increase IL-10-producing T cells in the colonic lamina propria. Thus, B. breve activates intestinal CD103+ DCs to produce IL-10 and IL-27 via the TLR2/MyD88 pathway thereby inducing IL-10-producing Tr1 cells in the large intestine. Oral B. breve administration ameliorated colitis in immunocompromised mice given naïve CD4+ T cells from wild-type mice, but not Il10
−/− mice. These findings demonstrate that B. breve prevents intestinal inflammation through the induction of intestinal IL-10-producing Tr1 cells. 相似文献
9.
10.
Kosuke Tanegashima Shiki Okamoto Yuki Nakayama Choji Taya Hiroshi Shitara Rie Ishii Hiromichi Yonekawa Yasuhiko Minokoshi Takahiko Hara 《PloS one》2010,5(4)
Background
CXCL14 is a chemoattractant for macrophages and immature dendritic cells. We recently reported that CXCL14-deficient (CXCL14 −/−) female mice in the mixed background are protected from obesity-induced hyperglycemia and insulin resistance. The decreased macrophage infiltration into visceral adipose tissues and the increased insulin sensitivity of skeletal muscle contributed to these phenotypes.Methodology/Principal Findings
In this study, we performed a comprehensive study for the body weight control of CXCL14 −/− mice in the C57BL/6 background. We show that both male and female CXCL14 −/− mice have a 7–11% lower body weight compared to CXCL14 +/− and CXCL14 +/+ mice in adulthood. This is mainly caused by decreased food intake, and not by increased energy expenditure or locomotor activity. Reduced body weight resulting from the CXCL14 deficiency was more pronounced in double mutant CXCL14−/− ob/ob and CXCL14 −/−Ay mice. In the case of CXCL14 −/−Ay mice, oxygen consumption was increased compared to CXCL14 +/−Ay mice, in addition to the reduced food intake. In CXCL14 −/− mice, fasting-induced up-regulation of Npy and Agrp mRNAs in the hypothalamus was blunted. As intracerebroventricular injection of recombinant CXCL14 did not change the food intake of CXCL14 −/− mice, CXCL14 could indirectly regulate appetite. Intriguingly, the food intake of CXCL14 −/− mice was significantly repressed when mice were transferred to a novel environment.Conclusions/Significance
We demonstrated that CXCL14 is involved in the body weight control leading to the fully obese phenotype in leptin-deficient or Ay mutant mice. In addition, we obtained evidence indicating that CXCL14 may play an important role in central nervous system regulation of feeding behavior. 相似文献11.
Different cis-Regulatory DNA Elements Mediate Developmental Stage- and Tissue-specific Expression of the Human COL2A1 Gene in Transgenic Mice
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Keith K.H. Leung Ling Jim Ng Ken K.Y. Ho Patrick P.L. Tam Kathryn S.E. Cheah 《The Journal of cell biology》1998,141(6):1291-1300
Expression of the type II collagen gene (human COL2A1, mouse Col2a1) heralds the differentiation of chondrocytes. It is also expressed in progenitor cells of some nonchondrogenic tissues during embryogenesis. DNA sequences in the 5′ flanking region and intron 1 are known to control tissue-specific expression in vitro, but the regulation of COL2A1 expression in vivo is not clearly understood. We have tested the regulatory activity of DNA sequences from COL2A1 on the expression of a lacZ reporter gene in transgenic mice. We have found that type II collagen characteristic expression of the transgene requires the enhancer activity of a 309-bp fragment (+2,388 to +2,696) in intron 1 in conjunction with 6.1-kb 5′ sequences. Different regulatory elements were found in the 1.6-kb region (+701 to +2,387) of intron 1 which only needs 90-bp 5′ sequences for tissue-specific expression in different components of the developing cartilaginous skeleton. Distinct positive and negative regulatory elements act together to control tissue-specific transgene expression in the developing midbrain neuroepithelium. Positive elements affecting expression in the midbrain were found in the region from −90 to −1,500 and from +701 to +2,387, whereas negatively acting elements were detected in the regions from −1,500 to −6,100 and +2,388 to +2,855. 相似文献
12.
Studies of human NK cells and their role in tumor suppression have largely been restricted to in vitro experiments which lack the complexity of whole organisms, or mouse models which differ significantly from humans. In this study we showed that, in contrast to C57BL/6 Rag2−/−/γc
−/− and NOD/Scid mice, newborn BALB/c Rag2−/−/γc
−/− mice can support the development of human NK cells and CD56+ T cells after intrahepatic injection with hematopoietic stem cells. The human CD56+ cells in BALB/c Rag2−/−/γc
−/− mice were able to produce IFN-γ in response to human IL-15 and polyI:C. NK cells from reconstituted Rag2−/−/γc
−/− mice were also able to kill and inhibit the growth of K562 cells in vitro and were able to produce IFN-γ in response to stimulation with K562 cells. In vivo, reconstituted Rag2−/−/γc
−/− mice had higher survival rates after K562 challenge compared to non-reconstituted Rag2−/−/γc
−/− mice and were able to control tumor burden in various organs. Reconstituted Rag2−/−/γc
−/− mice represent a model in which functional human NK and CD56+ T cells can develop from stem cells and can thus be used to study human disease in a more clinically relevant environment. 相似文献
13.
M J Parsons L McCormick L Janke A Howard L Bouchier-Hayes D R Green 《Cell death and differentiation》2013,20(9):1174-1182
Despite being the most evolutionarily conserved of the mammalian caspases, little is understood about the cellular function of caspase-2 in normal tissues or what role caspase-2 may have in the progression of human disease. It has been reported that deletion of the caspase-2 gene (Casp2), accelerates Eμ-myc lymphomagenesis in mice, and thus caspase-2 may act as a tumor suppressor in hematological malignancies. Here, we sought to extend these findings to epithelial cancers by examining the potential role of caspase-2 as a tumor suppressor in the mouse mammary carcinogenesis model; MMTV/c-neu. The rate of tumor acquisition was significantly higher in multiparous Casp2−/−/MMTV mice compared with Casp2+/+/MMTV and Casp2+/−/MMTV mice. Cells from Casp2−/−/MMTV tumors were often multinucleated and displayed bizarre mitoses and karyomegaly, while cells from Casp2+/+/MMTV and Casp2+/−/MMTV tumors never displayed this phenotype. Tumors from Casp2−/−/MMTV animals had a significantly higher mitotic index than tumors from Casp2+/+/MMTV and Casp2+/−/MMTV animals. Cell cycle analysis of Casp2−/− E1A/Ras-transformed mouse embryonic fibroblasts (MEF) also indicated a higher proliferative rate in the absence of caspase-2. In vitro assays further illustrated that MEF had increased genomic instability in the absence of caspase-2. This appears to be due to disruption of the p53 pathway because we observed a concomitant decrease in the induction of the p53 target genes, Pidd, p21 and Mdm2. Thus caspase-2 may function as a tumor suppressor, in part, through regulation of cell division and genomic stability. 相似文献
14.
Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos 总被引:3,自引:0,他引:3
Haiko P Makinen T Keskitalo S Taipale J Karkkainen MJ Baldwin ME Stacker SA Achen MG Alitalo K 《Molecular and cellular biology》2008,28(15):4843-4850
Lymphatic vessels play an important role in the regulation of tissue fluid balance, immune responses, and fat adsorption and are involved in diseases including lymphedema and tumor metastasis. Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) is necessary for development of the blood vasculature during early embryogenesis, but later, VEGFR-3 expression becomes restricted to the lymphatic vasculature. We analyzed mice deficient in both of the known VEGFR-3 ligands, VEGF-C and VEGF-D. Unlike the Vegfr3−/− embryos, the Vegfc−/−; Vegfd−/− embryos displayed normal blood vasculature after embryonic day 9.5. Deletion of Vegfr3 in the epiblast, using keratin 19 (K19) Cre, resulted in a phenotype identical to that of the Vegfr3−/− embryos, suggesting that this phenotype is due to defects in the embryo proper and not in placental development. Interestingly, the Vegfr3neo hypomorphic mutant mice carrying the neomycin cassette between exons 1 and 2 showed defective lymphatic development. Overexpression of human or mouse VEGF-D in the skin, under the K14 promoter, rescued the lymphatic hypoplasia of the Vegfc+/− mice in the K14-VEGF-D; Vegfc+/− compound mice, suggesting that VEGF-D is functionally redundant with VEGF-C in the stimulation of developmental lymphangiogenesis. Our results suggest VEGF-C- and VEGF-D-independent functions for VEGFR-3 in the early embryo. 相似文献
15.
Jixin Zhong Ping Yang Kenjiro Muta Robert Dong Mario Marrero Feili Gong Cong-Yi Wang 《PloS one》2010,5(3)
Given the importance of Jak2 in cell signaling, a critical role for Jak2 in immune cells especially dendritic cells (DCs) has long been proposed. The exact function for Jak2 in DCs, however, remained poorly understood as Jak2 deficiency leads to embryonic lethality. Here we established Jak2 deficiency in adult Cre+/+Jak2fl/fl mice by tamoxifen induction. Loss of Jak2 significantly impaired DC development as manifested by reduced BMDC yield, smaller spleen size and reduced percentage of DCs in total splenocytes. Jak2 was also crucial for the capacity of DCs to mediate innate immune response. Jak2−/− DCs were less potent in response to inflammatory stimuli and showed reduced capacity to secrete proinflammatory cytokines such as TNFα and IL-12. As a result, Jak2−/− mice were defective for the early clearance of Listeria after infection. However, their potency to mediate adaptive immune response was not affected. Unlike DCs, Jak2−/− macrophages showed similar capacity secretion of proinflammatory cytokines, suggesting that Jak2 selectively modulates innate immune response in a DC-dependent manner. Consistent with these results, Jak2−/− mice were remarkably resistant to lethal dose of LPS-induced septic shock, a deadly sepsis characterized by the excessive innate immune response, and adoptive transfer of normal DCs restored their susceptibility to LPS-induced septic shock. Mechanistic studies revealed that Jak2/SATA5 signaling is pivotal for DC development and maturation, while the capacity for DCs secretion of proinflammatory cytokines is regulated by both Jak2/STAT5 and Jak2/STAT6 signaling. 相似文献
16.
A tightly controlled balance between hematopoietic stem and progenitor cell compartments is required to maintain normal blood cell homeostasis throughout life, and this balance is regulated by intrinsic and extrinsic cellular factors. Cav-1 is a 22-kDa protein that is located in plasma membrane invaginations and is implicated in regulating neural stem cell and embryonic stem cell proliferation. However, the role of Cav-1 in hematopoietic stem cell (HSC) function is largely unknown. In this study, we used Cav-1−/− mice to investigate the role of Cav-1 in HSCs function during aging. The results showed that Cav-1−/− mice displayed a decreased percentage of B cells and an increased percentage of M cells in the bone marrow and peripheral blood, and these changes were due to an increased number of HSCs. FACS analysis showed that the numbers of Lin−Sca1+c-kit+ cells (LSKs), long-term HSCs (LT-HSCs), short-term HSCs and multipotent progenitors were increased in Cav-1−/− mice compared with Cav-1+/+ mice, and this increase became more pronounced with aging. An in vitro clonogenic assay showed that LT-HSCs from Cav-1−/− mice had reduced ability to self-renew. Consistently, an in vivo competitive transplantation assay showed that Cav-1−/− mice failed to reconstitute hematopoiesis. Moreover, a Cav-1 deletion disrupted the quiescence of LSKs and promoted cell cycle progression through G2/M phase. In addition, we found that Cav-1 deletion impaired the ability of HSCs to differentiate into mature blood cells. Taken together, these data suggest that Cav-1-deficient cells impaired HSCs quiescence and induced environmental alterations, which limited HSCs self-renewal and function. 相似文献
17.
18.
F Chen A Li S Gao D Hollern M Williams F Liu E A VanSickle E Andrechek C Zhang C Yang R Luo H Xiao 《Cell death & disease》2014,5(5):e1242
Estrogen receptor-alpha positive (ER+) breast cancers comprise the majority of human breast cancers, but molecular mechanisms underlying this subtype of breast cancers remain poorly understood. Here, we show that ER+ mammary luminal tumors arising in Tip30−/−MMTV-Neu mice exhibited increased enrichment of luminal progenitor gene signature. Deletion of the Tip30 gene increased proportion of mammary stem and progenitor cell populations, and raised susceptibility to ER+ mammary luminal tumors in female Balb/c mice. Moreover, Tip30−/− luminal progenitors displayed increases in propensity to differentiate to mature ER+ luminal cells and FoxA1 expression. Knockdown of FoxA1 expression in Tip30−/− progenitors by shRNA specific for FoxA1 reduced their differentiation toward ER+ mature luminal cells. Taken together, our results suggest that TIP30 is a key regulator for maintaining ER+ and ER−luminal pools in the mammary luminal lineage, and loss of it promotes expansion of ER+ luminal progenitors and mature cells and ER+ mammary tumorigenesis. 相似文献
19.
Cristina Cellurale Claire R. Weston Judith Reilly David S. Garlick D. Joseph Jerry Hayla K. Sluss Roger J. Davis 《PloS one》2010,5(8)
The cJun NH2-terminal kinase (JNK) signal transduction pathway has been implicated in mammary carcinogenesis. To test the role of JNK, we examined the effect of ablation of the Jnk1 and Jnk2 genes in a Trp53-dependent model of breast cancer using BALB/c mice. We detected no defects in mammary gland development in virgin mice or during lactation and involution in control studies of Jnk1−/− and Jnk2−/− mice. In a Trp53−/+ genetic background, mammary carcinomas were detected in 43% of control mice, 70% of Jnk1−/− mice, and 53% of Jnk2−/− mice. These data indicate that JNK1 and JNK2 are not essential for mammary carcinoma development in the Trp53−/+ BALB/c model of breast cancer. In contrast, this analysis suggests that JNK may partially contribute to tumor suppression. This conclusion is consistent with the finding that tumor-free survival of JNK-deficient Trp53−/+ mice was significantly reduced compared with control Trp53−/+ mice. We conclude that JNK1 and JNK2 can act as suppressors of mammary tumor development. 相似文献
20.
X Huang J Sun W Rong T Zhao D-h Li X Ding L-y Wu K Wu M Schachner Z-C Xiao L-l Zhu M Fan 《Cell death & disease》2013,4(8):e768
Close homologue of L1 (CHL1) is a transmembrane cell adhesion molecule that is critical for brain development and for the maintenance of neural circuits in adults. Recent studies revealed that CHL1 has diverse roles and is involved in the regulation of recovery after spinal cord injury. CHL1 expression was downregulated in the cerebral cortex, hypothalamus, and brain stem after the induction of acute hypoxia (AH). In the current study, we sought to address the role of CHL1 in regulating homeostasis responses to hypoxia using CHL1-knockout (CHL1−/−) mice. We found that, compared with wild-type littermates, CHL1−/− mice showed a dramatically lower mortality rate and an augmented ventilatory response after they were subjected to AH. Immunofluorescence staining revealed that CHL1 was expressed in the carotid body (CB), the key oxygen sensor in rodents, and CHL1 expression level in the CB as assayed by western blot was decreased after hypoxic exposure. The number of glomus cells and the expression of tyrosine hydroxylase (a marker for glomus cells) in the CB of CHL1−/− mice appeared to be increased compared with CHL1+/+ mice. In addition, in the ex vivo CB preparation, hypoxia induced a significantly greater afferent nerve discharge in CHL1−/− mice compared with CHL1+/+ mice. Furthermore, the arterial blood pressure and plasma catecholamine levels of CHL1−/− mice were also significantly higher than those of CHL1+/+ mice. Our findings first demonstrate that CHL1 is a novel intrinsic factor that is involved in CB function and in the ventilatory response to AH. 相似文献