STAT1 regulates p73‐mediated <i>Bax</i> gene expression

Soond, Surinder M.; Carroll, Christopher J.; Townsend, Paul A.; Sayan, Emre; Melino, Gerry; Behrmann, Iris; Knight, Richard; Latchman, David S.; Stephanou, Anastasis

doi:10.1016/j.febslet.2007.02.049

Cited by 22 publications

(25 citation statements)

References 58 publications

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“…Previous studies have shown that STAT1 cooperates with p53 to induce apoptosis by selectively enhancing the transcriptional activity of p53 on p53 target gene promoters bearing an ASPP2 signature, such as Bax (31) and Noxa (32). Because LPS-induced STAT1 activity induces ASPP2 expression, we tested whether LPS-induced nuclear ASPP2 and p53 may play a proapoptotic role in response to inflammatory stimuli.…”

Section: Lps Induces Nuclear Aspp2 Expression In a Mouse Model Of Matmentioning

confidence: 99%

STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression

Turnquist¹,

Wang²,

Severson³

et al. 2014

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

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Significance Two of the most debilitating and scientifically challenging diseases of the 21st century are cancer and neurodegeneration. Although cancer results from excessive cell growth, neurodegeneration is a consequence of excessive cell loss. Dysfunction of the same key regulators, including oncogenes and tumor suppressors, may cause both diseases. We report that LPS and IFN induce apoptosis-stimulating protein of p53 with signature sequences of ankyrin repeat-, SH3 domain-, and proline-rich region-containing protein 2 (ASPP2) transcription through a signal transducer and activator of transcription 1 (STAT1) -dependent but NF-κB RELA/p65-independent pathway and that ASPP2 mediates LPS-induced apoptosis. Thus, the identified STAT1/ASPP2 pathway reveals an important function of ASPP2 in the cellular response to inflammation and infection and connects neuroinflammation to cell polarity and tumor suppression.

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Section: Lps Induces Nuclear Aspp2 Expression In a Mouse Model Of Matmentioning

confidence: 99%

STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression

Turnquist¹,

Wang²,

Severson³

et al. 2014

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

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“…Following transfection, cleared supernatents were prepared, assayed and analysed by Western blotting as outlined previously. 64 Statistical analysis. Luciferase data was analysed using Microsoft Excel (Microsoft) to determine the standard error around the mean, before the results were translated to fold activation of relative light units over basal control experiments.…”

Section: Methodsmentioning

confidence: 99%

“…Transfected or non-transfected mammalian cells were treated exactly as outlined previously. 64 In vitro kinase assays GST fusion proteins. Purified GST fusion proteins (immobilised on sepharose) were incubated in 1 ml of PLK kinase buffer (lacking ATP) for 5 minutes on ice after which they were harvested by centrifugation at 400 g for 20 seconds, all of the liquid phase removed and discarded.…”

Section: Methodsmentioning

confidence: 99%

“…GST-p73 fusion proteins were purified from transformed BL-21 LysS cells (Promega) induced and isolated as previously outlined. 64 GST co-precipitation and co-immunoprecipitation assays. Transfected or non-transfected mammalian cells were treated exactly as outlined previously.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were fixed in Paraformaldehyde (PFA), permeablised in PFA, 0.1% v/v Triton-X100 and stained using antigen specific antibodies, DAPI and images captures as outlined previously. 64 Luciferase reporter assays. Human p21-luciferase, Bax-luciferase and the p53 responsive elements from the 14-3-3σ gene (fused to the luciferase gene) were generous gifts from Dr. G. Melino and Dr B. Vogelstein (Johns Hopkins Oncology Center, Maryland, USA) 49 (respectively) and were used at 250 ng per transfection.…”

Section: Methodsmentioning

confidence: 99%

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p73-mediated transcriptional activity is negatively regulated by Polo-like kinase 1

Soond¹,

Barry²,

Melino³

et al. 2008

Cell Cycle

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Trans-activating (TA) p73 is a member of the p53 family of transcription factors and has been implicated in cell cycle regulation, apoptosis and developmental processes. Although TAp73 positively regulates an overlapping repertoire of genes regulated by p53, TAp73 has been observed to be paradoxically overexpressed in a number of tumor cell types arousing much interest in the post-translational regulation of TAp73 transcriptional activity. Here, we present novel findings that show TAp73 can interact and co-localise, with Polo-Like Kinase 1 (PLK1) and that TAp73 is phosphorylated by this kinase on Threonine-27 (Thr-27) within the TA domain. Using reporter assays and Electrophoretic Mobility Shift Assays (EMSA), our findings suggest that TAp73-mediated activation of the p21 cip/waf , 14-3-3σ and Bax gene promoters is abrogated by expressed PLK1 for which post-translational modification of TAp73 Thr-27 appears to be a key step in MCF7 cells. Thus highlighting a potential mechanism that uniquely contributes to PLK1-mediated and phosphor-dependent transcriptional deactivation of expressed TAp73.

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Decreased sensitivity of 17p‐deleted chronic lymphocytic leukemia cells to a small molecule BCL‐2 antagonist ABT‐737

Kojima

Duvvuri

Ruvolo

et al. 2011

Cancer

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BACKGROUND Despite the high complete response rates with fludarabine-based regimens, relapse is inevitable in chronic lymphocytic leukemia (CLL). Relapsed patients often acquire 17p deletions [del(17p)], which are closely associated with TP53 mutations. Wild-type p53 upregulates and activates BAX, and it downregulates and inactivates BCL-2. The small-molecule BCL-2 inhibitor ABT-737 induces apoptosis in a BAX- and BAK-dependent manner. The role of p53 in sensitivity of CLL cells to BCL-2 inhibition has not been extensively investigated. METHODS We investigated an association of del(17p) with ABT-737 sensitivity in CLL cells from 50 patients. Stable p53 and BAX knockdown cells were used for the mechanistic studies. RESULTS CLL cells with del(17p) are less sensitive to ABT-737-induced BAX activation and apoptosis than those without del(17p) (39.0 ± 7.3% versus 63.7 ± 2.9% specific Annexin V induction; P < .01). A positive correlation between the degrees of apoptosis induced by ABT-737 and by the p53-activating MDM2 antagonist Nutlin-3a (r = 0.75; P < .0001) was observed. CLL cells with del(17p) expressed lower levels of BAX than those without (0.67 ± 0.12 versus 1.27 ± 0.10 in relative protein expression levels; P < .01). Knockdown of p53 or BAX in leukemia cells resulted in decreased apoptosis induced by ABT-737. CONCLUSIONS Data indicate that p53 dysfunction may lead to decreased apoptosis induction by ABT-737.

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STAT1 regulates p73‐mediated Bax gene expression

Cited by 22 publications

References 58 publications

STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression

STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression

p73-mediated transcriptional activity is negatively regulated by Polo-like kinase 1

Decreased sensitivity of 17p‐deleted chronic lymphocytic leukemia cells to a small molecule BCL‐2 antagonist ABT‐737

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