HER4 D-box sequences regulate mitotic progression and degradation of the nuclear HER4 cleavage product s80HER4
| Autor: | Rebecca S. Muraoka-Cook, Carty Husted, H. Shelton Earp, Debra Hunter, Melissa Sandahl, William A. Rearick, Leah C. Miraglia, Karen E. Strunk |
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| Rok vydání: | 2007 |
| Předmět: |
G2 Phase
Cancer Research Small interfering RNA animal structures Receptor ErbB-4 Antigens Polyomavirus Transforming Neuregulin-1 Amino Acid Motifs Green Fluorescent Proteins Mitosis Biology Cleavage (embryo) Article Cell Line Tumor medicine Humans Cell Line Transformed Cell Nucleus Ubiquitin Cell cycle Molecular biology Ubiquitin ligase Cell biology Protein Structure Tertiary ErbB Receptors Cell nucleus medicine.anatomical_structure Oncology biology.protein Signal transduction Nuclear localization sequence Cell Division HeLa Cells |
| Zdroj: | Cancer research. 67(14) |
| ISSN: | 0008-5472 |
| Popis: | Heregulin-mediated activation of HER4 initiates receptor cleavage (releasing an 80-kDa HER4 intracellular domain, s80HER4, containing nuclear localization sequences) and results in G2-M delay by unknown signaling mechanisms. We report herein that s80HER4 contains a functional cyclin B–like sequence known as a D-box, which targets proteins for degradation by anaphase-promoting complex (APC)/cyclosome, a multisubunit ubiquitin ligase. s80HER4 ubiquitination and proteasomal degradation occurred during mitosis but not during S phase. Inhibition of an APC subunit (APC2) using short interfering RNA knockdown impaired s80HER4 degradation. Mutation of the s80HER4 D-box sequence stabilized s80HER4 during mitosis, and s80HER4-dependent growth inhibition via G2-M delay was significantly greater with the D-box mutant. Polyomavirus middle T antigen–transformed HC11 cells expressing s80HER4 resulted in smaller, less proliferative, more differentiated tumors in vivo than those expressing kinase-dead s80HER4 or the empty vector. Cells expressing s80HER4 with a disrupted D-box did not form tumors, instead forming differentiated ductal structures. These results suggest that cell cycle–dependent degradation of s80HER4 limits its growth-inhibitory action, and stabilization of s80HER4 enhances tumor suppression, thus providing a link between HER4-mediated growth inhibition and cell cycle control. [Cancer Res 2007;67(14):6582–90] |
| Databáze: | OpenAIRE |
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