Growth inhibition by CDK-cyclin and PCNA binding domains of p21 occurs by distinct mechanisms and is regulated by ubiquitin-proteasome pathway.

Rousseau, D; Cannella, D; Boulaire, J; Fitzgerald, P; Fotedar, A; Fotedar, R

Rousseau, D; Cannella, D; Boulaire, J; Fitzgerald, P; Fotedar, A; Fotedar, R.

Afiliación

Rousseau D; Institut de Biologie Structurale J-P Ebel, Grenoble, France.

Oncogene ; 18(21): 3290-302, 1999 May 27.

Article en En | MEDLINE | ID: mdl-10359535

RESUMEN

The CDK inhibitor, p21(WAF1/Cip1) blocks cell cycle progression. In vitro, the N-terminus of p21 binds and inhibits CDK-cyclin kinase activity, whereas the C-terminus binds and inhibits PCNA (proliferating cell nuclear antigen) function. PCNA is essential for processivity of both DNA polymerase delta and epsilon. We have performed a detailed analysis of growth inhibition by the N- and C-terminal regions of p21, and determined whether the N- and C-terminal regions mediate this effect by different mechanisms. Expression of either the N- or the C-terminal region of p21 inhibits DNA synthesis and cell growth, but not as efficiently as full length p21. The effectiveness of the two p21 domains is dependent on their stability which is determined by the ubiquitin-proteasome pathway. The stabilization of the N- and C-terminal region of p21 increases their effectiveness as inhibitors of DNA synthesis to levels comparable to full length p21. Inhibition of DNA synthesis by the N-terminal region of p21 involves suppression of E2F activity. In contrast, inhibition by the C-terminal region of p21 is not accompanied by suppression of E2F activity, but is mediated via PCNA binding. The C-terminal region of p21 therefore inhibits cell growth by a mechanism distinct from that of the N-terminal region containing the CDK-cyclin inhibitory domain.

Asunto(s)

Quinasas CDC2-CDC28; Proteínas Portadoras; Proteínas de Ciclo Celular; Quinasas Ciclina-Dependientes/metabolismo; Ciclinas/metabolismo; Cisteína Endopeptidasas/metabolismo; Proteínas de Unión al ADN; Complejos Multienzimáticos/metabolismo; Antígeno Nuclear de Célula en Proliferación/metabolismo; Proteínas Serina-Treonina Quinasas/metabolismo; Ubiquitinas/metabolismo; Células 3T3; Animales; Sitios de Unión; División Celular; Quinasa 2 Dependiente de la Ciclina; Inhibidor p21 de las Quinasas Dependientes de la Ciclina; Ciclinas/genética; Factores de Transcripción E2F; Vectores Genéticos; Humanos; Ratones; Mutagénesis; Complejo de la Endopetidasa Proteasomal; Proteínas Recombinantes de Fusión/genética; Proteínas Recombinantes de Fusión/metabolismo; Proteína 1 de Unión a Retinoblastoma; Fase S; Factor de Transcripción DP1; Factores de Transcripción/metabolismo; Transcripción Genética; Células Tumorales Cultivadas

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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cisteína Endopeptidasas / Ubiquitinas / Proteínas Portadoras / Proteínas Serina-Treonina Quinasas / Ciclinas / Antígeno Nuclear de Célula en Proliferación / Quinasas Ciclina-Dependientes / Proteínas de Ciclo Celular / Quinasas CDC2-CDC28 / Proteínas de Unión al ADN Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 1999 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Reino Unido

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