Altered subcellular localization of tumor-specific cyclin E isoforms affects cyclin-dependent kinase 2 complex formation and proteasomal regulation.
Cancer Res
; 69(7): 2817-25, 2009 Apr 01.
Article
de En
| MEDLINE
| ID: mdl-19318554
ABSTRACT
In tumors, alternative translation and posttranslational proteolytic cleavage of full-length cyclin E (EL) produces tumorigenic low molecular weight cyclin E (LMW-E) isoforms that lack a portion of the EL amino-terminus containing a nuclear localization sequence. Therefore, we hypothesized that LMW-E isoforms have altered subcellular localization. To explore our hypothesis, we compared EL versus LMW-E localization in cell lysates and in vivo using fractionation and protein complementation assays. Our results reveal that LMW-E isoforms preferentially accumulate in the cytoplasm where they bind the cyclin E kinase partner, cyclin-dependent kinase 2 (Cdk2), and have associated kinase activity. The nuclear ubiquitin ligase Fbw7 targets Cdk2-bound cyclin E for degradation; thus, we examined if altered subcellular localization affected LMW-E degradation. We found that cytoplasmic LMW-E/Cdk2 was less susceptible to Fbw7-mediated degradation. One implication of our findings is that altered LMW-E and LMW-E/Cdk2 subcellular localization may lead to aberrant LMW-E protein interactions, regulation, and activity, ultimately contributing to LMW-E tumorigenicity.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Cycline E
/
Proteasome endopeptidase complex
/
Kinase-2 cycline-dépendante
/
Tumeurs
Limites:
Humans
Langue:
En
Journal:
Cancer Res
Année:
2009
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique