Suppression of Tumorigenesis and Induction of p15ink4b by Smad4/DPC4 in Human Pancreatic Cancer Cells
Purpose: The tumor suppressor gene Smad4 / DPC4 , a key transcription factorin transforming growth factor β (TGF-β) signaling cascades,is inactivated in 50% of pancreatic adenocarcinomas. We seek to determine the role of Smad4 / DPC4 in the suppression of tumor cell growth and in the regulation of T...
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| Veröffentlicht in: | Clinical cancer research 2002-11, Vol.8 (11), p.3628-3638 |
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| creator | BAILU PENG FLEMING, Jason B ROBERTSON, Kimberly D CHIAO, Paul J BRESLIN, Tara GRAU, Ana M FOJIOKA, Shuichi ABBRUZZESE, James L EVANS, Douglas B AYERS, Dan WATHEN, Kyle TIANAI WU |
| description | Purpose: The tumor suppressor gene Smad4 / DPC4 , a key transcription factorin transforming growth factor β (TGF-β) signaling cascades,is inactivated in 50% of pancreatic
adenocarcinomas. We seek to determine the role of Smad4 / DPC4 in the suppression of tumor cell growth and in the regulation of TGF-β-mediated expression of cell-cycle regulatory genes
p15 ink4b and p21 waf1 .
Experimental Design: Smad4 / DPC4 is overexpressed by adenoviral infection in CFPac-1 pancreatic cancer cells, in which the Smad4 / DPC4 is homozygously deleted, and in Capan-1 pancreatic cancer cells, in which Smad4 / DPC4 is not expressed. Expression of the TGF-β downstream target gene p21 waf1 , regulation of the p15 ink4b promoter, anchorage-independent growth, and tumorigenesis were examined.
Results: We demonstrate that expression of Smad4 / DPC4 in Capan-1 cells reduced anchorage-independent growth by more than 50%, and inhibited xenograft tumor growth. However, overexpression
of Smad4 / DPC4 did not inhibit CFPac-1 cell growth. Interestingly, Smad4/DPC4 induced expression of p15 ink4b , p21 waf1 , and TGF-β-responsive reporter gene in Capan-1 but not in CFPac-1 cells. Furthermore, we found a previously unidentified
Smad4 binding element (SBE) located in the region between −356 and −329 bp of the p15 ink4b promoter. The p15 ink4b promoter reporter gene assays revealed that Smad4-dependent transcriptional activation is mediated by this SBE, which indicates
that p15 ink4b is one of the downstream target genes regulated by Smad/DPC4.
Conclusion: These results explain the role of Smad4 / DPC4 in TGF-β-mediated inhibition of cell proliferation in vitro and in vivo . Moreover, these results suggest that Smad4 / DPC4 -mediated tumor suppression and induction of TGF-β-regulated cell-cycle-inhibitory genes may depend on additional factors
that are absent in CFPac-1 cells. |
| format | Article |
| fullrecord | <record><control><sourceid>pascalfrancis_highw</sourceid><recordid>TN_cdi_pascalfrancis_primary_14023100</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>14023100</sourcerecordid><originalsourceid>FETCH-LOGICAL-h630-9097ed7d6189afb5e8655e815925939ece3c72d65eb4cfcb7a2f394a1fef67323</originalsourceid><addsrcrecordid>eNotkN9LwzAcxIMobk7_h7wIvhTzu82jVN0GAwfbe0nTb9Zom5VkRfbfW9ye7uCO48PdoDmVMs84U_J28iQvMiI4m6GHlL4JoYIScY9mlAmmlZRzBLtxGCKk5I8BHx3ej_0x-gMESD5hExq8Ds1oT9d4oNKHH1Hj-ox3vWnE6_u2FNgHvBp7E_DWBBvBnLzF5WQh4hK6Lj2iO2e6BE9XXaD958e-XGWbr-W6fNtkreIk00Tn0OSNooU2rpZQTIhQUKmZ1FyDBW5z1igJtbDO1rlhjmthqAOncs74Aj1fZgeTrOlcnBB8qoboexPPFRWEcUrI1Hu59Fp_aH99hMr-w04_gIm2rYqK0oorVvA_ZzFigQ</addsrcrecordid><sourcetype>Index Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Suppression of Tumorigenesis and Induction of p15ink4b by Smad4/DPC4 in Human Pancreatic Cancer Cells</title><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>American Association for Cancer Research</source><source>Alma/SFX Local Collection</source><creator>BAILU PENG ; FLEMING, Jason B ; ROBERTSON, Kimberly D ; CHIAO, Paul J ; BRESLIN, Tara ; GRAU, Ana M ; FOJIOKA, Shuichi ; ABBRUZZESE, James L ; EVANS, Douglas B ; AYERS, Dan ; WATHEN, Kyle ; TIANAI WU</creator><creatorcontrib>BAILU PENG ; FLEMING, Jason B ; ROBERTSON, Kimberly D ; CHIAO, Paul J ; BRESLIN, Tara ; GRAU, Ana M ; FOJIOKA, Shuichi ; ABBRUZZESE, James L ; EVANS, Douglas B ; AYERS, Dan ; WATHEN, Kyle ; TIANAI WU</creatorcontrib><description>Purpose: The tumor suppressor gene Smad4 / DPC4 , a key transcription factorin transforming growth factor β (TGF-β) signaling cascades,is inactivated in 50% of pancreatic
adenocarcinomas. We seek to determine the role of Smad4 / DPC4 in the suppression of tumor cell growth and in the regulation of TGF-β-mediated expression of cell-cycle regulatory genes
p15 ink4b and p21 waf1 .
Experimental Design: Smad4 / DPC4 is overexpressed by adenoviral infection in CFPac-1 pancreatic cancer cells, in which the Smad4 / DPC4 is homozygously deleted, and in Capan-1 pancreatic cancer cells, in which Smad4 / DPC4 is not expressed. Expression of the TGF-β downstream target gene p21 waf1 , regulation of the p15 ink4b promoter, anchorage-independent growth, and tumorigenesis were examined.
Results: We demonstrate that expression of Smad4 / DPC4 in Capan-1 cells reduced anchorage-independent growth by more than 50%, and inhibited xenograft tumor growth. However, overexpression
of Smad4 / DPC4 did not inhibit CFPac-1 cell growth. Interestingly, Smad4/DPC4 induced expression of p15 ink4b , p21 waf1 , and TGF-β-responsive reporter gene in Capan-1 but not in CFPac-1 cells. Furthermore, we found a previously unidentified
Smad4 binding element (SBE) located in the region between −356 and −329 bp of the p15 ink4b promoter. The p15 ink4b promoter reporter gene assays revealed that Smad4-dependent transcriptional activation is mediated by this SBE, which indicates
that p15 ink4b is one of the downstream target genes regulated by Smad/DPC4.
Conclusion: These results explain the role of Smad4 / DPC4 in TGF-β-mediated inhibition of cell proliferation in vitro and in vivo . Moreover, these results suggest that Smad4 / DPC4 -mediated tumor suppression and induction of TGF-β-regulated cell-cycle-inhibitory genes may depend on additional factors
that are absent in CFPac-1 cells.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>PMID: 12429655</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Biological and medical sciences ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Fundamental and applied biological sciences. Psychology ; Molecular and cellular biology</subject><ispartof>Clinical cancer research, 2002-11, Vol.8 (11), p.3628-3638</ispartof><rights>2003 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14023100$$DView record in Pascal Francis$$Hfree_for_read</backlink></links><search><creatorcontrib>BAILU PENG</creatorcontrib><creatorcontrib>FLEMING, Jason B</creatorcontrib><creatorcontrib>ROBERTSON, Kimberly D</creatorcontrib><creatorcontrib>CHIAO, Paul J</creatorcontrib><creatorcontrib>BRESLIN, Tara</creatorcontrib><creatorcontrib>GRAU, Ana M</creatorcontrib><creatorcontrib>FOJIOKA, Shuichi</creatorcontrib><creatorcontrib>ABBRUZZESE, James L</creatorcontrib><creatorcontrib>EVANS, Douglas B</creatorcontrib><creatorcontrib>AYERS, Dan</creatorcontrib><creatorcontrib>WATHEN, Kyle</creatorcontrib><creatorcontrib>TIANAI WU</creatorcontrib><title>Suppression of Tumorigenesis and Induction of p15ink4b by Smad4/DPC4 in Human Pancreatic Cancer Cells</title><title>Clinical cancer research</title><description>Purpose: The tumor suppressor gene Smad4 / DPC4 , a key transcription factorin transforming growth factor β (TGF-β) signaling cascades,is inactivated in 50% of pancreatic
adenocarcinomas. We seek to determine the role of Smad4 / DPC4 in the suppression of tumor cell growth and in the regulation of TGF-β-mediated expression of cell-cycle regulatory genes
p15 ink4b and p21 waf1 .
Experimental Design: Smad4 / DPC4 is overexpressed by adenoviral infection in CFPac-1 pancreatic cancer cells, in which the Smad4 / DPC4 is homozygously deleted, and in Capan-1 pancreatic cancer cells, in which Smad4 / DPC4 is not expressed. Expression of the TGF-β downstream target gene p21 waf1 , regulation of the p15 ink4b promoter, anchorage-independent growth, and tumorigenesis were examined.
Results: We demonstrate that expression of Smad4 / DPC4 in Capan-1 cells reduced anchorage-independent growth by more than 50%, and inhibited xenograft tumor growth. However, overexpression
of Smad4 / DPC4 did not inhibit CFPac-1 cell growth. Interestingly, Smad4/DPC4 induced expression of p15 ink4b , p21 waf1 , and TGF-β-responsive reporter gene in Capan-1 but not in CFPac-1 cells. Furthermore, we found a previously unidentified
Smad4 binding element (SBE) located in the region between −356 and −329 bp of the p15 ink4b promoter. The p15 ink4b promoter reporter gene assays revealed that Smad4-dependent transcriptional activation is mediated by this SBE, which indicates
that p15 ink4b is one of the downstream target genes regulated by Smad/DPC4.
Conclusion: These results explain the role of Smad4 / DPC4 in TGF-β-mediated inhibition of cell proliferation in vitro and in vivo . Moreover, these results suggest that Smad4 / DPC4 -mediated tumor suppression and induction of TGF-β-regulated cell-cycle-inhibitory genes may depend on additional factors
that are absent in CFPac-1 cells.</description><subject>Biological and medical sciences</subject><subject>Cell physiology</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Molecular and cellular biology</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><recordid>eNotkN9LwzAcxIMobk7_h7wIvhTzu82jVN0GAwfbe0nTb9Zom5VkRfbfW9ye7uCO48PdoDmVMs84U_J28iQvMiI4m6GHlL4JoYIScY9mlAmmlZRzBLtxGCKk5I8BHx3ej_0x-gMESD5hExq8Ds1oT9d4oNKHH1Hj-ox3vWnE6_u2FNgHvBp7E_DWBBvBnLzF5WQh4hK6Lj2iO2e6BE9XXaD958e-XGWbr-W6fNtkreIk00Tn0OSNooU2rpZQTIhQUKmZ1FyDBW5z1igJtbDO1rlhjmthqAOncs74Aj1fZgeTrOlcnBB8qoboexPPFRWEcUrI1Hu59Fp_aH99hMr-w04_gIm2rYqK0oorVvA_ZzFigQ</recordid><startdate>20021101</startdate><enddate>20021101</enddate><creator>BAILU PENG</creator><creator>FLEMING, Jason B</creator><creator>ROBERTSON, Kimberly D</creator><creator>CHIAO, Paul J</creator><creator>BRESLIN, Tara</creator><creator>GRAU, Ana M</creator><creator>FOJIOKA, Shuichi</creator><creator>ABBRUZZESE, James L</creator><creator>EVANS, Douglas B</creator><creator>AYERS, Dan</creator><creator>WATHEN, Kyle</creator><creator>TIANAI WU</creator><general>American Association for Cancer Research</general><scope>IQODW</scope></search><sort><creationdate>20021101</creationdate><title>Suppression of Tumorigenesis and Induction of p15ink4b by Smad4/DPC4 in Human Pancreatic Cancer Cells</title><author>BAILU PENG ; FLEMING, Jason B ; ROBERTSON, Kimberly D ; CHIAO, Paul J ; BRESLIN, Tara ; GRAU, Ana M ; FOJIOKA, Shuichi ; ABBRUZZESE, James L ; EVANS, Douglas B ; AYERS, Dan ; WATHEN, Kyle ; TIANAI WU</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h630-9097ed7d6189afb5e8655e815925939ece3c72d65eb4cfcb7a2f394a1fef67323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Biological and medical sciences</topic><topic>Cell physiology</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Molecular and cellular biology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>BAILU PENG</creatorcontrib><creatorcontrib>FLEMING, Jason B</creatorcontrib><creatorcontrib>ROBERTSON, Kimberly D</creatorcontrib><creatorcontrib>CHIAO, Paul J</creatorcontrib><creatorcontrib>BRESLIN, Tara</creatorcontrib><creatorcontrib>GRAU, Ana M</creatorcontrib><creatorcontrib>FOJIOKA, Shuichi</creatorcontrib><creatorcontrib>ABBRUZZESE, James L</creatorcontrib><creatorcontrib>EVANS, Douglas B</creatorcontrib><creatorcontrib>AYERS, Dan</creatorcontrib><creatorcontrib>WATHEN, Kyle</creatorcontrib><creatorcontrib>TIANAI WU</creatorcontrib><collection>Pascal-Francis</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>BAILU PENG</au><au>FLEMING, Jason B</au><au>ROBERTSON, Kimberly D</au><au>CHIAO, Paul J</au><au>BRESLIN, Tara</au><au>GRAU, Ana M</au><au>FOJIOKA, Shuichi</au><au>ABBRUZZESE, James L</au><au>EVANS, Douglas B</au><au>AYERS, Dan</au><au>WATHEN, Kyle</au><au>TIANAI WU</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Suppression of Tumorigenesis and Induction of p15ink4b by Smad4/DPC4 in Human Pancreatic Cancer Cells</atitle><jtitle>Clinical cancer research</jtitle><date>2002-11-01</date><risdate>2002</risdate><volume>8</volume><issue>11</issue><spage>3628</spage><epage>3638</epage><pages>3628-3638</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Purpose: The tumor suppressor gene Smad4 / DPC4 , a key transcription factorin transforming growth factor β (TGF-β) signaling cascades,is inactivated in 50% of pancreatic
adenocarcinomas. We seek to determine the role of Smad4 / DPC4 in the suppression of tumor cell growth and in the regulation of TGF-β-mediated expression of cell-cycle regulatory genes
p15 ink4b and p21 waf1 .
Experimental Design: Smad4 / DPC4 is overexpressed by adenoviral infection in CFPac-1 pancreatic cancer cells, in which the Smad4 / DPC4 is homozygously deleted, and in Capan-1 pancreatic cancer cells, in which Smad4 / DPC4 is not expressed. Expression of the TGF-β downstream target gene p21 waf1 , regulation of the p15 ink4b promoter, anchorage-independent growth, and tumorigenesis were examined.
Results: We demonstrate that expression of Smad4 / DPC4 in Capan-1 cells reduced anchorage-independent growth by more than 50%, and inhibited xenograft tumor growth. However, overexpression
of Smad4 / DPC4 did not inhibit CFPac-1 cell growth. Interestingly, Smad4/DPC4 induced expression of p15 ink4b , p21 waf1 , and TGF-β-responsive reporter gene in Capan-1 but not in CFPac-1 cells. Furthermore, we found a previously unidentified
Smad4 binding element (SBE) located in the region between −356 and −329 bp of the p15 ink4b promoter. The p15 ink4b promoter reporter gene assays revealed that Smad4-dependent transcriptional activation is mediated by this SBE, which indicates
that p15 ink4b is one of the downstream target genes regulated by Smad/DPC4.
Conclusion: These results explain the role of Smad4 / DPC4 in TGF-β-mediated inhibition of cell proliferation in vitro and in vivo . Moreover, these results suggest that Smad4 / DPC4 -mediated tumor suppression and induction of TGF-β-regulated cell-cycle-inhibitory genes may depend on additional factors
that are absent in CFPac-1 cells.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>12429655</pmid><tpages>11</tpages></addata></record> |
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| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research; Alma/SFX Local Collection |
| subjects | Biological and medical sciences Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Fundamental and applied biological sciences. Psychology Molecular and cellular biology |
| title | Suppression of Tumorigenesis and Induction of p15ink4b by Smad4/DPC4 in Human Pancreatic Cancer Cells |
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