Retinoic acid induces neuronal differentiation of embryonal carcinoma cells by reducing proteasome-dependent proteolysis of the cyclin-dependent inhibitor p27

G Baldassarre; A Boccia; P Bruni; C Sandomenico; M V Barone; S Pepe; T Angrisano; B Belletti; M L Motti; A Fusco; G Viglietto

Retinoic acid induces neuronal differentiation of embryonal carcinoma cells by reducing proteasome-dependent proteolysis of the cyclin-dependent inhibitor p27

Cell Growth Differ. 2000 Oct;11(10):517-26.

Authors

G Baldassarre¹, A Boccia, P Bruni, C Sandomenico, M V Barone, S Pepe, T Angrisano, B Belletti, M L Motti, A Fusco, G Viglietto

Affiliation

¹ Servizio Oncologia Sperimentale E, Istituto Nazionale Tumori, Naples, Italy.

PMID: 11063125

Abstract

Retinoic acid (RA) treatment of embryonal carcinoma cell line NTERA-2 clone D1 (NT2/D1) induces growth arrest and terminal differentiation along the neuronal pathway. In the present study, we provide a functional link between RA and p27 function in the control of neuronal differentiation in NT2/D1 cells. We report that RA enhances p27 expression, which results in increased association with cyclin E/cyclin-dependent kinase 2 complexes and suppression of their activity; however, antisense clones, which have greatly reduced RA-dependent p27 inducibility (NT2-p27AS), continue to synthesize DNA and are unable to differentiate properly in response to RA as determined by lack of neurite outgrowth and by the failure to modify surface antigens. As to the mechanism involved in RA-dependent p27 upregulation, our data support the concept that RA reduces p27 protein degradation through the ubiquitin/proteasome-dependent pathway. Taken together, these findings demonstrate that in embryonal carcinoma cells, p27 expression is required for growth arrest and proper neuronal differentiation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Carcinoma, Embryonal / drug therapy*
Carcinoma, Embryonal / genetics
Carcinoma, Embryonal / metabolism
Carcinoma, Embryonal / pathology*
Cell Cycle Proteins*
Cell Differentiation / drug effects
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases / antagonists & inhibitors
Cysteine Endopeptidases / genetics
Cysteine Endopeptidases / metabolism
Gene Expression Regulation, Neoplastic / drug effects
Humans
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / metabolism
Multienzyme Complexes / genetics
Multienzyme Complexes / metabolism
Neurons / metabolism
Neurons / pathology*
Proteasome Endopeptidase Complex
Tretinoin / pharmacology*
Tretinoin / therapeutic use
Tumor Cells, Cultured
Tumor Suppressor Proteins*

Substances

Antineoplastic Agents
Cell Cycle Proteins
Microtubule-Associated Proteins
Multienzyme Complexes
Tumor Suppressor Proteins
Cyclin-Dependent Kinase Inhibitor p27
Tretinoin
Cyclin-Dependent Kinases
Cysteine Endopeptidases
Proteasome Endopeptidase Complex