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Suppression of tumorigenesis and induction of p15(ink4b) by Smad4/DPC4 in human pancreatic cancer cells.

Publication ,  Journal Article
Peng, B; Fleming, JB; Breslin, T; Grau, AM; Fojioka, S; Abbruzzese, JL; Evans, DB; Ayers, D; Wathen, K; Wu, T; Robertson, KD; Chiao, PJ
Published in: Clin Cancer Res
November 2002

PURPOSE: The tumor suppressor gene Smad4/DPC4, a key transcription factorin transforming growth factor beta (TGF-beta) 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-beta-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-beta 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-beta-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-beta-mediated inhibition of cell proliferation in vitro and in vivo. Moreover, these results suggest that Smad4/DPC4-mediated tumor suppression and induction of TGF-beta-regulated cell-cycle-inhibitory genes may depend on additional factors that are absent in CFPac-1 cells.

Duke Scholars

Published In

Clin Cancer Res

ISSN

1078-0432

Publication Date

November 2002

Volume

8

Issue

11

Start / End Page

3628 / 3638

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Cells, Cultured
  • Transforming Growth Factor beta
  • Transfection
  • Transcriptional Activation
  • Trans-Activators
  • Time Factors
  • Smad4 Protein
  • Signal Transduction
  • Promoter Regions, Genetic
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Peng, B., Fleming, J. B., Breslin, T., Grau, A. M., Fojioka, S., Abbruzzese, J. L., … Chiao, P. J. (2002). Suppression of tumorigenesis and induction of p15(ink4b) by Smad4/DPC4 in human pancreatic cancer cells. Clin Cancer Res, 8(11), 3628–3638.
Peng, Bailu, Jason B. Fleming, Tara Breslin, Ana M. Grau, Shuichi Fojioka, James L. Abbruzzese, Douglas B. Evans, et al. “Suppression of tumorigenesis and induction of p15(ink4b) by Smad4/DPC4 in human pancreatic cancer cells.Clin Cancer Res 8, no. 11 (November 2002): 3628–38.
Peng B, Fleming JB, Breslin T, Grau AM, Fojioka S, Abbruzzese JL, et al. Suppression of tumorigenesis and induction of p15(ink4b) by Smad4/DPC4 in human pancreatic cancer cells. Clin Cancer Res. 2002 Nov;8(11):3628–38.
Peng, Bailu, et al. “Suppression of tumorigenesis and induction of p15(ink4b) by Smad4/DPC4 in human pancreatic cancer cells.Clin Cancer Res, vol. 8, no. 11, Nov. 2002, pp. 3628–38.
Peng B, Fleming JB, Breslin T, Grau AM, Fojioka S, Abbruzzese JL, Evans DB, Ayers D, Wathen K, Wu T, Robertson KD, Chiao PJ. Suppression of tumorigenesis and induction of p15(ink4b) by Smad4/DPC4 in human pancreatic cancer cells. Clin Cancer Res. 2002 Nov;8(11):3628–3638.

Published In

Clin Cancer Res

ISSN

1078-0432

Publication Date

November 2002

Volume

8

Issue

11

Start / End Page

3628 / 3638

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Cells, Cultured
  • Transforming Growth Factor beta
  • Transfection
  • Transcriptional Activation
  • Trans-Activators
  • Time Factors
  • Smad4 Protein
  • Signal Transduction
  • Promoter Regions, Genetic