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  Induction of the Cdk inhibitor p21 by LY83583 inhibits tumor cell proliferation in a p53-independent manner

Lodygin, D., Menssen, A., & Hermeking, H. (2002). Induction of the Cdk inhibitor p21 by LY83583 inhibits tumor cell proliferation in a p53-independent manner. Journal of Clinical Investigation, 110(11), 1717-1727.

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Genre: Journal Article
Alternative Title : J. Clin. Invest.

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 Creators:
Lodygin, D.1, Author              
Menssen, A.2, Author              
Hermeking, H.1, Author              
Affiliations:
1Former Research Groups, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565145              
2Ullrich, Axel / Molecular Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565172              

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 Abstract: Using microarray analysis, we have detected downregulation of several components of the cGMP signaling pathway during replicative senescence of primary human diploid fibroblasts (HDFs). Therefore, the effect of pharmacological inhibition of cGMP synthesis was analyzed in HDFs. Treatment with 6-anilino- 5,8-quinolinequinone (LY83583, referred to as LY hereafter), a previously described inhibitor of guanylate cyclase, induced cellular senescence. Microarray analysis revealed that LY treatment induced the Cdk inhibitor p21(WAF1/SDI/CIP1). In colorectal cancer cells, transcription of p21 was induced by LY in a p53-independent manner. Furthermore, p21, but not p53, was required for inhibition of proliferation by LY. The lack of p53 involvement suggests that LY does not induce DNA damage. Growth inhibition was also observed in malignant melanoma and breast cancer cell lines. Functional inactivation of the retinoblastoma tumor-suppressor protein, an effector of p21- mediated cell-cycle inhibition, converted LY-induced growth arrest to apoptosis. These results suggest that LY, or derivatives, may be useful therapeutic agents for the treatment of tumors.

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Language(s): eng - English
 Dates: 2002-12
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 41686
ISI: 000179706500019
 Degree: -

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Title: Journal of Clinical Investigation
  Alternative Title : J. Clin. Invest.
Source Genre: Journal
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Pages: - Volume / Issue: 110 (11) Sequence Number: - Start / End Page: 1717 - 1727 Identifier: ISSN: 0021-9738