The Role of Stat3 in Apoptosis and Mammary Gland Involution

Chapman, Rachel S.; Lourenco, Paula C.; Tonner, Elizabeth; Flint, David; Selbert, Stefan; Takeda, Kyoshi; Akira, Shizuo; Clarke, Alan Richard; Watson, Christine J.

doi:10.1007/0-306-46832-8_16

Cited by 107 publications

(91 citation statements)

References 26 publications

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“…It is possible that stage of progression through the cell cycle, or other transcription factors such as signal transducer and activator of transcription 3 (STAT3), may be involved. STAT3 has been implicated in apoptosis (Akira, 2000;Chapman et al, 2000), and CD40 ligation in B cells results in tyrosine phosphorylation of Janus tyrosine kinase3, leading to the phosphorylation and subsequent activation of STAT3 (Hanissian and Geha, 1997). We have previously reported NF-B and AP-1 activation in response to CD40 ligation in primary human cholangiocytes (Afford et al, 2001), and further experiments have confirmed that both hepatocytes and cholangiocytes show similar signaling responses to CD40 activation (our unpublished data for cholangiocytes).…”

Section: Discussionsupporting

confidence: 59%

Differential Induction of Nuclear Factor-κB and Activator Protein-1 Activity after CD40 Ligation Is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation

Choudhury

Russell

Randhawa

et al. 2003

MBoC

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CD40, a tumor necrosis factor receptor superfamily member, is up-regulated on intraheptatic endothelial cells (IHEC) and epithelial cells during inflammatory liver disease, and there is evidence that the functional outcome of CD40 ligation differs between cell types. Ligation of CD40 on cholangiocytes or hepatocytes results in induction of Fas-mediated apoptosis, whereas ligation of IHEC CD40 leads to enhanced chemokine secretion and adhesion molecule expression. We now report that differential activation of two transcription factors, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), in primary human hepatocytes or IHEC, is associated with and may explain, in part, the different responses of these cell types to CD40 ligation. CD40 ligation induced a rise in NF-κB activity in hepatocytes ,which peaked at 2 h and returned to baseline by 24 h; however, IHEC CD40 ligation resulted in a sustained up-regulation of NF-κB (>24 h). In hepatocytes, CD40 ligation led to sustained up-regulation of AP-1 activity >24 h associated with increased protein levels of RelA (p65), c-Jun, and c-Fos, whereas no induction of AP-1 activity was observed in IHECs. Analysis of mitogen-activated protein kinase phosphorylation (phospho-extracellular signal-regulated kinase 1/2 and phospho-c-Jun NH2-terminal kinase 1/2) and expression of inhibitor κBα were entirely consistent, and thus confirmed the profiles of NF-κB and AP-1 signaling and the effects of the selective inhibitors assessed using electrophoretic mobility shift assay or Western immunoblotting. CD40 ligation resulted in induction of apoptosis in hepatocytes after 24 h, but on IHECs, CD40 ligation resulted in proliferation. Inhibition of (CD40-mediated) NF-κB activation prevented IHEC proliferation and led to induction of apoptosis. Selective extracellular signal-regulated kinase and c-Jun NH2-terminal kinase inhibitors reduced levels of apoptosis in (CD40-stimulated) hepatocytes by ∼50%. We conclude that differential activation of these two transcription factors in response to CD40 ligation is associated with differences in cell fate. Transient activation of NF-κB and sustained AP-1 activation is associated with apoptosis in hepatocytes, whereas prolonged NF-κB activation and a lack of AP-1 activation in IHECs result in proliferation.

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Section: Discussionsupporting

confidence: 59%

Differential Induction of Nuclear Factor-κB and Activator Protein-1 Activity after CD40 Ligation Is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation

Choudhury

Russell

Randhawa

et al. 2003

MBoC

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“…MMTV-AKT1 mice universally exhibited varying degrees of delayed involution, which coincided with elevated cyclin D1 levels, increased AKT1 activation and an increased number of mitotic cells (Figures 5 and 7). The delay in involution correlated with the persistence of phospho-Tyr705-STAT3, which disappeared upon involution (Li et al, 1997;Chapman et al, 1999). There was a direct correlation between prolonged expression of activated AKT and cyclin D1 in the involuting mammary gland of both founder lines (Figures 6 and 7).…”

Section: Discussionmentioning

confidence: 83%

Delayed mammary gland involution in MMTV-AKT1 transgenic mice

et al. 2002

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AKT1/protein kinase Ba is a protein-serine/threonine kinase that regulates multiple targets involved in cell survival and cell cycle progression in a variety of cell types including breast cancer cells. To explore the role of Akt1 in mammary gland function and tumorigenesis, transgenic mice were generated that express human AKT1 under the control of the MMTV promoter. Virgin transgenic mice did not exhibit a dominant phenotype, but upon cessation of lactation, a notable delay in involution occurred compared to age-matched nontransgenic mice. The delay in involution coincided with increased hyperplasia as evidenced by an increased number of binucleated epithelial cells and a marked elevation in cyclin D1 expression in mammary epithelium. The delayed involution phenotype corresponded to increased phosphorylation of Thr308 in AKT1 and Ser136 in BAD, but not phosphorylation of Ser21 in GSK-3a. There was no evidence of mammary dysplasia or neoplasia during the lifespan of multiparous transgenic mice. These data suggest that AKT1 is involved in cell survival in the lactating and involuting mammary gland, but that overexpression of AKT1 alone is insu cient to induce transformation.

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“…The induction of involution in the mammary gland is accompanied by a strong P-STAT3 activation and results in the massive apoptosis of alveoli. Sumoylation results in an increased protein stability and possibly points at a role for PIAS3 to limit P-STAT3 activity at the end of the involution process (33). From these data, it is tempting to speculate that PIAS3 protects normal cells from P-STAT3 addiction by fine tuning P-STAT3 activity and preventing its oncogenic effects.…”

Section: Discussionmentioning

confidence: 99%

The Intracellular Delivery of a Recombinant Peptide Derived from the Acidic Domain of PIAS3 Inhibits STAT3 Transactivation and Induces Tumor Cell Death

Borghouts

Tittmann

Delis

et al. 2010

Molecular Cancer Research

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Signaling components, which confer an "addiction" phenotype on cancer cells, represent promising drug targets. The transcription factor signal transducers and activators of transcription 3 (STAT3) is constitutively activated in many different types of tumor cells and its activity is indispensible in a large fraction. We found that the expression of the endogenous inhibitor of STAT3, protein inhibitor of activated STAT3 (PIAS3), positively correlates with STAT3 activation in normal cells. This suggests that PIAS3 controls the extent and the duration of STAT3 activity in normal cells and thus prevents its oncogenic function. In cancer cells, however, the expression of PIAS3 is posttranscriptionally suppressed, possibly enhancing the oncogenic effects of activated STAT3. We delimited the interacting domains of STAT3 and PIAS3 and identified a short fragment of the COOH-terminal acidic region of PIAS3, which binds strongly to the coiled-coil domain of STAT3. This PIAS3 fragment was used to derive the recombinant STAT3-specific inhibitor rPP-C8. The addition of a protein transduction domain allowed the efficient internalization of rPP-C8 into cancer cells. This resulted in the suppression of STAT3 target gene expression, in the inhibition of migration and proliferation, and in the induction of apoptosis at low concentrations [half maximal effective concentration (EC 50 ), <3 μmol/L]. rPP-C8 did not affect normal fibroblasts and represents an interesting lead for the development of novel cancer drugs targeting the coiled-coil domain of STAT3. Mol Cancer Res; 8(4); 539-53. ©2010 AACR.

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The Role of Stat3 in Apoptosis and Mammary Gland Involution

Cited by 107 publications

References 26 publications

Differential Induction of Nuclear Factor-κB and Activator Protein-1 Activity after CD40 Ligation Is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation

Differential Induction of Nuclear Factor-κB and Activator Protein-1 Activity after CD40 Ligation Is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation

Delayed mammary gland involution in MMTV-AKT1 transgenic mice

The Intracellular Delivery of a Recombinant Peptide Derived from the Acidic Domain of PIAS3 Inhibits STAT3 Transactivation and Induces Tumor Cell Death

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