Cell Growth Arrest and Induction of Cyclin-Dependent Kinase Inhibitor p21
            <sup>WAF1/CIP1</sup>
            Mediated by STAT1

Chin, Y. Eugene; Kitagawa, Motoo; Su, Wu Chou; You, Zhi Hao; Iwamoto, Yoshiki; Fu, Xin

doi:10.1126/science.272.5262.719

Cited by 769 publications

(632 citation statements)

References 38 publications

Supporting

Mentioning

596

Contrasting

Unclassified

Order By: Relevance

“…Less is known about the role of STATs in growth factor signaling than in cytokine signaling, but both growth stimulatory and inhibitory pathways are stimulated (Wagner et al, 1990;Chin et al, 1996;Su et al, 1997). The mechanism of tyrosine phosphorylation of STATs in growth factor treated cells is also unclear.…”

Section: Introductionmentioning

confidence: 99%

STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation

1999

View full text Add to dashboard Cite

Activation of the platelet-derived growth factor (PDGF) receptor tyrosine kinase induces tyrosine phosphorylation of Signal Transducer and Activator of Transcription (STAT) proteins. Since the PDGF receptor also activates the Src tyrosine kinase, it is possible that Src mediates tyrosine phosphorylation of STATs in PDGFtreated cells. Consistent with a role for Src in STAT activation, we found that a PDGF receptor juxtamembrane tyrosine residue required for Src activation is necessary and su cient for activation of STATs 1 and 3. To test the Src requirement further, we made other mutations in the PDGF receptor juxtamembrane region that increased or decreased Src binding. In epithelial and ®broblast cells, PDGF activated STAT1, 3 and 6 in the absence of detectable binding and activation of Src. In addition, PDGF induced c-myc RNA expression and DNA synthesis even though Src was not detectably activated. The activation of MAP kinase and the induction of c-fos gene expression both correlated with STAT but not Src activation by the receptor. We conclude that juxtamembrane tyrosine phosphorylation is necessary for both Src tyrosine kinase and STAT activation by the bPDGF receptor, but that both processes are regulated independently by this region.

show abstract

Section: Introductionmentioning

confidence: 99%

STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation

1999

View full text Add to dashboard Cite

show abstract

“…In Fig 2A, the transcripts of p21 cip1/waf1 -related genes were analyzed in details, such as EGR1 , STAT1 [20], p53 [21,22], and cyclins . Significantly, EGR1 and STAT1 were decreased by EBER1 across all probe sets that were used in the Affymetrix chip to monitor a single gene.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, EBER1 might suppress p21 cip1/waf1 through the wild-type p53 in KE, but not the mutant-type p53 in LE [29,30]. Since the binding sites on the p21 cip1/waf1 promoter for EGR1 [18,19] and STAT1 [20] and p53 [21,22] are already known, further studies are necessary to reveal how EBER1 suppresses p53, EGR1, and STAT1, and whether or not post-transcriptional regulations of p21 cip1/waf1 are also involved.…”

Section: Resultsmentioning

confidence: 99%

EBV-positive Hodgkin lymphoma is associated with suppression of p21cip1/waf1 and a worse prognosis

Liu

Huang

et al. 2010

Mol Cancer

View full text Add to dashboard Cite

BackgroundAbout 30-50% of Hodgkin lymphomas (HLs) harbor the Epstein-Barr virus (EBV), but the impact of EBV infection on clinical outcomes has been unclear. EBV-encoded small RNAs (EBERs) are presented in all EBV-infected cells, but their functions are still less understood.ResultsEBER1 was transfected into two HL cell lines, KMH2 and L428, and microarrays were used to screen for EBER1-induced changes. We found that EBER1 suppressed p21cip1/waf1 transcription in HL cell lines. In addition, positive regulators of p21cip1/waf1 transcription, such as p53, EGR1, and STAT1, were decreased. Suppression of p21cip1/waf1 in the EBER1+ HL cell lines was associated with increased resistance to histone deacetylase inhibitors or proteasome inhibitors, drugs known to cause apoptosis by increasing p21cip1/waf1 levels. On biopsy specimens, EBV+ HLs had weaker expression of both p21cip1/waf1 and active caspase 3. Clinically, suppression of p21cip1/waf1 in EBV+ HLs was associated with a worse 2-year disease-free survival rate (45% for EBV+ HLs vs. 77% for EBV- HLs, p = 0.002).ConclusionAlthough the underlying mechanisms are still relatively unclear, EBER1 inhibits p21cip1/waf1 transcription and prevents apoptosis through down-regulation of p53, EGR1, and STAT1. The anti-apoptotic activity of EBER1 may be important in the rescue of Reed-Sternberg cells from drug-induced apoptosis and in the clinical behaviors of EBV+ HLs.

show abstract

“…Following activation, it binds to the promotor of the gene encoding the cyclin -dependent p21 kinase inhibitor, inducing its transcription. 20 Concurrently, activation of STAT1 signaling pathway has been shown to cause expression of Caspase 1 and apoptosis. 21 Although cell lines derived from the hepatocarcinoma developed by ASV mice were found to be sensitive to IFN -, 15 and this correlated with STAT1 expression (data not shown ), apoptosis was not observed.…”

Section: Discussionmentioning

confidence: 99%

Regression of primary hepatocarcinoma in cancer-prone transgenic mice by local interferon-γ delivery is associated with macrophages recruitment and nitric oxide production

et al. 2001

View full text Add to dashboard Cite

The clinical potential of tumor therapies must be evaluated using animal models closely resembling human cancers. We investigated the impact of locally delivered interferon -(IFN-) on primary hepatocarcinoma spontaneously developed by T -SV40 transgenic mice. A single intratumor injection of adenovirus IFN -was sufficient enough to induce in vivo production of biologically active IFN -, as assessed by STAT1 activation. IFN -secretion led to the regression of primary tumor, principally by apoptosis of tumor hepatocytes. The lack of T -cells infiltrates in the liver upon treatment excluded a role of a specific immune response. In contrast, indirect pathways may include tumoricidal function of macrophages. Indeed, they were massively recruited in the entire liver under IFN -treatment; transmigration through hepatic blood vessels could be observed and co -localization with damaged hepatocytes was obvious. This correlated with nonparenchymal liver cell iNOS expression and high level of NO in hepatic extracts. Moreover, in vitro experiments showed that NO releasing agents induced cell death of freshly isolated tumor hepatocytes, suggesting that NO could be one of the major effector molecules. Altogether, these observations defined an important role of IFN -in controlling tumor development in a model of primary hepatocarcinoma.

show abstract

Cell Growth Arrest and Induction of Cyclin-Dependent Kinase Inhibitor p21 ^WAF1/CIP1 Mediated by STAT1

Cited by 769 publications

References 38 publications

STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation

STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation

EBV-positive Hodgkin lymphoma is associated with suppression of p21cip1/waf1 and a worse prognosis

Regression of primary hepatocarcinoma in cancer-prone transgenic mice by local interferon-γ delivery is associated with macrophages recruitment and nitric oxide production

Contact Info

Product

Resources

About

Cell Growth Arrest and Induction of Cyclin-Dependent Kinase Inhibitor p21 WAF1/CIP1 Mediated by STAT1

Cited by 769 publications

References 38 publications

STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation

STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation

EBV-positive Hodgkin lymphoma is associated with suppression of p21cip1/waf1 and a worse prognosis

Regression of primary hepatocarcinoma in cancer-prone transgenic mice by local interferon-γ delivery is associated with macrophages recruitment and nitric oxide production

Contact Info

Product

Resources

About

Cell Growth Arrest and Induction of Cyclin-Dependent Kinase Inhibitor p21 ^WAF1/CIP1 Mediated by STAT1