Induction of the Cdk inhibitor p21 by LY83583 inhibits tumor cell proliferation in a p53-independent manner.
J Clin Invest
; 110(11): 1717-27, 2002 Dec.
Article
en En
| MEDLINE
| ID: mdl-12464677
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Ciclinas
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Quinasas Ciclina-Dependientes
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Inhibidores Enzimáticos
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Aminoquinolinas
Límite:
Humans
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Newborn
Idioma:
En
Revista:
J Clin Invest
Año:
2002
Tipo del documento:
Article
País de afiliación:
Alemania