Overexpression of TIAP/m-survivin in thymocytes enhances cell proliferation

Hikita, Satosi; Hatano, Masahiko; Inoue, Atsushi; Sekita, Nobuyuki; Kobayashi, Koichi S.; Otaki, Masayuki; Ogasawara, Takeshi; Okada, Seiji; Hirasawa, Hiroyuki; Tokuhisa, Takeshi

doi:10.1016/s0161-5890(02)00111-6

Cited by 14 publications

(13 citation statements)

References 26 publications

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“…These and other data suggest that survivin regulates G 1 -S transition in T lymphocytes (8,9). In addition, transgenic expression of survivin in thymocytes under the control of the lck promoter induces hyperproliferation in response to phorbol 12-myristate 13-acetate and ionomycin without an effect on apoptosis (74)…”

Section: Role Of Survivin Int Lymphocytessupporting

confidence: 51%

Survivin, a cancer target with an emerging role in normal adult tissues

Fukuda

Pelus

2006

Molecular Cancer Therapeutics

429

360

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Survivin, an inhibitor of apoptosis protein, is highly expressed in most cancers and associated with chemotherapy resistance, increased tumor recurrence, and shorter patient survival, making antisurvivin therapy an attractive cancer treatment strategy. However, growing evidence indicates that survivin is expressed in normal adult cells, particularly primitive hematopoietic cells, T lymphocytes, polymorphonuclear neutrophils, and vascular endothelial cells, and may regulate their proliferation or survival. In preclinical animal models, targeted antisurvivin therapies show efficacy without overt toxicity. However, consequences of prolonged survivin disruption in normal cells, particularly those associated with continuous renewal, have not been clearly determined. Understanding the role of survivin in normal versus malignant cells will be important in identifying strategies that maximally disrupt survivin in cancer cells with minimal effect on normal tissues. In this review, we summarize the prognostic relevance of survivin in cancer that justifies the pursuit of antisurvivin therapies and discuss differences in survivin expression between normal and cancer cells. We subsequently review expression of survivin in normal adult tissues and evaluate preclinical antisurvivin therapies reported to date in light of emerging roles for survivin in normal physiology, particularly hematopoiesis, angiogenesis, and immune function. [Mol Cancer Ther 2006;5(5):1087 -98]

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Section: Role Of Survivin Int Lymphocytessupporting

confidence: 51%

Survivin, a cancer target with an emerging role in normal adult tissues

Fukuda

Pelus

2006

Molecular Cancer Therapeutics

429

360

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“…These genes include many genes previously shown to be down-regulated in DP thymocytes by TCR or positive selection, such as survivin, rag2, TdT, and ROR␥t (39)(40)(41)(42). In general, a good correlation occurred between genes repressed by in vitro TCR stimulation and genes repressed during positive selection.…”

Section: Genes Repressed In Response To Tcr or Positive-selection Sigmentioning

confidence: 93%

Distinct transcriptional programs in thymocytes responding to T cell receptor, Notch, and positive selection signals

Huang

Winoto

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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T cell antigen receptor (TCR) signaling is necessary but not sufficient to promote the positive selection of CD4 ؉ CD8 ؉ thymocytes into CD4 ؉ or CD8 ؉ mature T cells. Notch signaling has also been implicated as a potential regulator of both CD4͞CD8 T cell development and TCR signaling. However, the relationship between positive selection, TCR signaling, and Notch remains unclear. Here we use DNA microarray analysis to compare gene expression changes in CD4 ؉ CD8 ؉ double-positive thymocytes undergoing positive selection, TCR stimulation, and Notch activation. We find that the genes induced during positive selection can be resolved into two distinct sets. One set, which we term ''TCR-induced,'' is also induced by in vitro TCR stimulation and contains a large proportion of transcription factors. A second set, which we term ''positive-selection-induced,'' is not induced by in vitro TCR simulation and contains a large proportion of genes involved in signal transduction pathways. Genes induced by Notch activity overlap substantially with genes induced during positive selection. We also find that Notch activity potentiates the effects of TCR stimulation on gene expression. These results help to identify TCR-and positive-selection-specific transcriptional events and help to clarify the relationship between positive selection and Notch.microarray ͉ gene expression profile ͉ negative selection

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“…5,20,21 Survivin also increases the proliferation of primary thymocytes. 22 The cyclin-dependent kinase inhibitor p21 WAF1/Cip1 is a key regulator of cell cycle and cell survival. [23][24][25][26][27] It is also involved in microtubule-dependent checkpoints, and p21-deficiency results in deformed nuclear architecture and polyploidy.…”

Section: Introductionmentioning

confidence: 99%

Survivin regulates hematopoietic progenitor cell proliferation through p21WAF1/Cip1-dependent and -independent pathways

Fukuda

Mantel

Pelus

2004

Blood

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The cyclin-dependent kinase inhibitor p21 WAF1/Cip1 and Survivin enhance granulocyte macrophage colony-forming unit (CFU-GM) cell cycle and proliferation and have been implicated as antiapoptotic proteins. We investigated the relationships between p21 and Survivin in primary CFU-GM and c-kit ؉ , lineage-negative (Lin ؊ ) cells and demonstrate p21-dependent and -independent pathways whereby Survivin regulates progenitor cell proliferation. Ectopic Survivin enhanced p21 ؉/؉ CFU-GM formation and expansion of ckit ؉ , Lin ؊ cells, whereas p21 gene loss abrogated these effects, indicating a p21 requirement. A dominant-negative form of Survivin and p21 gene deletion accelerated the loss of CFU-GM upon growth factor deprivation, and wild-type Survivin overexpression inhibited apoptosis of p21 ؉/؉ CFU-GM and c-kit ؉ , Lin ؊ cells but not p21 ؊/؊ cells, suggesting that both Survivin and p21 block apoptosis of progenitors and that Survivin-mediated antiapoptosis requires p21. In contrast to the p21-dependent antiapoptotic effects, Survivin increased the proportion of CFU-GM in S-phase in both p21 ؉/؉ and p21 ؊/؊ cells. IntroductionSurvivin is a member of the inhibitor of apoptosis protein (IAP) family and has been implicated in antiapoptosis, cell division, and cell-cycle control. [1][2][3][4][5] Survivin blocks apoptosis in cancer cells treated with various apoptotic stimuli, 2,4,[6][7][8] and Survivin disruption induces apoptosis in tumor models in vivo. [9][10][11] Survivin also plays a role in regulating cell division, 1,12-15 serving as a kinetochore-associated passenger protein. 16 Disruption of Survivin in HeLa cells prolongs metaphase and induces polyploidy, whereas overexpression changes microtubule dynamics. 15 Survivin is barely detectable in most differentiated normal adult cells but is aberrantly enhanced in most cancers. 2 We recently reported that Survivin is expressed in normal adult bone marrow and umbilical cord blood CD34 ϩ cells and that its expression can be up-regulated by hematopoietic growth factors. 17 Survivin expression increases with CD34 ϩ cell-cycle progression and reaches maximum during the G 2 /M phase; however, unlike cancer cells, normal CD34 ϩ cells express Survivin in all phases of the cell cycle. 17 Detailed analyses of Survivin expression in quiescent CD34 ϩ cells revealed that its expression is up-regulated before Ki67 Ϫ G 0 cells enter G 1 , 18,19 suggesting cell-cycle-phaseindependent regulation. Overexpression of Survivin in primary mouse bone marrow cells increases total granulocyte macrophage colony-forming unit (CFU-GM) and the proportion of CFU-GM in S-phase, whereas an antisense Survivin construct has the opposite effect, suggesting that Survivin can regulate hematopoietic progenitor cell proliferation through cell cycle control. 18 Consistent with our observations, Survivin enhances cell-cycle progression in hepatoma cells through effects on cdk2/cyclin E activation and retinoblastoma protein (Rb) phosphorylation. 5,20,21 Survivin also increases the proliferation of primary...

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Overexpression of TIAP/m-survivin in thymocytes enhances cell proliferation

Cited by 14 publications

References 26 publications

Survivin, a cancer target with an emerging role in normal adult tissues

Survivin, a cancer target with an emerging role in normal adult tissues

Distinct transcriptional programs in thymocytes responding to T cell receptor, Notch, and positive selection signals

Survivin regulates hematopoietic progenitor cell proliferation through p21WAF1/Cip1-dependent and -independent pathways

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