Pim-1 Negatively Regulates the Activity of PTP-U2S Phosphatase and Influences Terminal Differentiation and Apoptosis of Monoblastoid Leukemia Cells

Wang, Zeping; Bhattacharya, Nandini; Meyer, Maria; Seimiya, Hiroyuki; Tsuruo, Takashi; Tonani, Jessica A.; Magnuson, Nancy S.

doi:10.1006/abbi.2001.2370

Cited by 41 publications

(38 citation statements)

References 41 publications

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“…The final concentration of ATP was 10 μmol/L. Kinase assays to determine IC 50 values were performed by Reaction Biology Corp. Purified recombinant kinases were incubated with serial 3-fold dilutions of test compounds starting at a final concentration of 100 μmol/L. ATP concentration was 10 μmol/L unless otherwise indicated.…”

Section: Kinome Screen and Kinase Assaysmentioning

confidence: 99%

“…1E), showing significant cytotoxicity of 65D4 to DU-145 cells. To investigate the growth inhibitory properties of 65D4, prostate cancer cells were treated with different concentrations of 65D4 for 3 days and the IC 50 for growth was then determined using the SRB assay. Figure 1F shows that 65D4 inhibits the growth of DU-145 cells, with an IC 50 of 2 μmol/L.…”

Section: Selection Of 21a8 21h7 and 65d4mentioning

confidence: 99%

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PIM Kinase Inhibitors Downregulate STAT3Tyr705 Phosphorylation

Chang

Kanwar

Feng

et al. 2010

Molecular Cancer Therapeutics

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Using a cell-based high-throughput screen designed to detect small chemical compounds that inhibit cell growth and survival, we identified three structurally related compounds, 21A8, 21H7, and 65D4, with differential activity on cancer versus normal cells. Introduction of structural modifications yielded compound M-110, which inhibits the proliferation of prostate cancer cell lines with IC 50 s of 0.6 to 0.9 μmol/L, with no activity on normal human peripheral blood mononuclear cells up to 40 μmol/L. Screening of 261 recombinant kinases and subsequent analysis revealed that M-110 is a selective inhibitor of the PIM kinase family, with preference for PIM-3. The prostate cancer cell line DU-145 and the pancreatic cancer cell line MiaPaCa2 constitutively express activated STAT3 (pSTAT3 , we used PIM-1-, PIM-2-, or PIM-3-specific siRNA and showed that knockdown of PIM-3, but not of PIM-1 or PIM-2, in DU-145 cells results in a significant downregulation of pSTAT3 Tyr705. The phosphorylation of STAT5 on Tyr694 in 22Rv1 cells is not affected by M-110 or SGI-1776, suggesting specificity for pSTAT3 Tyr705 . These results identify a novel role for PIM-3 kinase as a positive regulator of STAT3 signaling and suggest that PIM-3 inhibitors cause growth inhibition of cancer cells by downregulating the expression of pSTAT3 Tyr705

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Section: Kinome Screen and Kinase Assaysmentioning

confidence: 99%

Section: Selection Of 21a8 21h7 and 65d4mentioning

confidence: 99%

PIM Kinase Inhibitors Downregulate STAT3Tyr705 Phosphorylation

Chang

Kanwar

Feng

et al. 2010

Molecular Cancer Therapeutics

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“…PIM-1 is able to phosphorylate itself (26,27) through its recently identified novel autophosphorylation site that diverges from its consensus phosphorylation motif (28). Several substrates of PIM-1 have been identified, including p21Cip1/WAF1 (29,30), Cdc25A (31), PTPU2 (32), NuMA (33), C-TAK1 (34), and Cdc25C (35), indicating PIM-1 is involved in the cell proliferation at both G 1 /S and G 2 /M transition. PIM-1 also contributes to the regulation of cell apoptosis and antiapoptotic activity (32,36,37).…”

Section: Introductionmentioning

confidence: 99%

PIM-1–specific mAb suppresses human and mouse tumor growth by decreasing PIM-1 levels, reducing Akt phosphorylation, and activating apoptosis

Hu¹,

Li²,

Vandervalk³

et al. 2009

J. Clin. Invest.

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Provirus integration site for Moloney murine leukemia virus (PIM1) is a proto-oncogene that encodes a serine/ threonine kinase with multiple cellular functions. Overexpression of PIM-1 plays a critical role in progression of prostatic and hematopoietic malignancies. Here we describe the generation of a mAb specific for GST-PIM-1, which reacted strongly with most human and mouse cancer tissues and cell lines of prostate, breast, and colon origin but only weakly (if at all) with normal tissues. The mAb binds to PIM-1 in the cytosol and nucleus as well as to PIM-1 on the surface of human and murine cancer cells. Treatment of human and mouse prostate cancer cell lines with the PIM-1-specific mAb resulted in disruption of PIM-1/Hsp90 complexes, decreased PIM-1 and Hsp90 levels, reduced Akt phosphorylation at Ser473, reduced phosphorylation of Bad at Ser112 and Ser136, and increased cleavage of caspase-9, an indicator of activation of the mitochondrial cell death pathway. The mAb induced cancer cell apoptosis and synergistically enhanced antitumor activity when used in combination with cisplatin and epirubicin. In tumor models, the PIM-1-specific mAb substantially inhibited growth of the human prostate cancer cell line DU145 in SCID mice and the mouse prostate cancer cell TRAMP-C1 in C57BL/6 mice. These findings are important because they provide what we believe to be the first in vivo evidence that treatment of prostate cancer may be possible by targeting PIM-1 using an Ab-based therapy.

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“…S4). Alternatively, the antagonizing phosphotases may differ for these sites and several of which are inhibited by PIM-1 kinase activity (34,71,72). Despite the fact that both isoforms could phosphorylate Ser-213, only PIM-1S was capable of promoting AR degradation.…”

Section: Discussionmentioning

confidence: 99%

Differential Regulation of Androgen Receptor by PIM-1 Kinases via Phosphorylation-dependent Recruitment of Distinct Ubiquitin E3 Ligases

Linn

Yang

Xie

et al. 2012

Journal of Biological Chemistry

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Background:The androgen receptor (AR) plays a critical role in prostate cancer development and progression. Results: Oncogenic PIM-1 kinases directly interact with AR and induce AR phosphorylation at multiple residues. Conclusion: PIM-1 kinases differentially modulate AR activity via phosphorylation-dependent recruitment of distinct ubiquitin E3 ligases. Significance: Our findings provide new insights into mechanisms by which AR activity may be regulated in prostate cancer cells.

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Pim-1 Negatively Regulates the Activity of PTP-U2S Phosphatase and Influences Terminal Differentiation and Apoptosis of Monoblastoid Leukemia Cells

Cited by 41 publications

References 41 publications

PIM Kinase Inhibitors Downregulate STAT3Tyr705 Phosphorylation

PIM Kinase Inhibitors Downregulate STAT3Tyr705 Phosphorylation

PIM-1–specific mAb suppresses human and mouse tumor growth by decreasing PIM-1 levels, reducing Akt phosphorylation, and activating apoptosis

Differential Regulation of Androgen Receptor by PIM-1 Kinases via Phosphorylation-dependent Recruitment of Distinct Ubiquitin E3 Ligases

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