In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 14 ( 2007-07-15), p. 6582-6590
Kurzfassung:
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]
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/0008-5472.CAN-06-4145
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2007
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
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