Regulation of BIRC5 and its isoform BIRC5-2B in neuroblastoma.
We analysed the expression of BIRC5 and BIRC5-2B in primary neuroblastoma (NB) tumors and NB model systems. In tumors, overexpression of BIRC5 correlated closely with its isoform BIRC5-2B. Expression of both transcripts was stage-dependent, associated with poor prognosis and with the expression of the transcription factor E2F1. In cell culture, we identified BIRC5 as a direct transcriptional target of activating E2Fs, primarily when p21(Cip1) and p27(Kip1), two other E2F1 targets, are strongly suppressed. Deregulated MYCN indirectly induces BIRC5 through suppression of CDKN1A/p21(Cip1) and induction of Skp2, which in turn favors the degradation of p27(Kip1). In addition, increased BIRC5 protein stability via phosphorylation is mediated by expression of E2F targets such as CDC2. In line with this, selective knock down of CDC2 inhibited BIRC5 abundance and suppressed its anti-apoptotic activities. We conclude that BIRC5 is induced via a functional cooperation between MYCN and E2F1.
Eckerle
Isabella
I
Department of Tumor Genetics, German Cancer Research Center, Heidelberg, Germany.
Muth
Daniel
D
Batzler
Julia
J
Henrich
Kai-Oliver
KO
Lutz
Werner
W
Fischer
Matthias
M
Witt
Olaf
O
Schwab
Manfred
M
Westermann
Frank
F
D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D016203:CDC2 Protein Kinase; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D050687:E2F1 Transcription Factor / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D000071447:N-Myc Proto-Oncogene Protein; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D009687:Nuclear Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D000077022:Survivin; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome
C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D019926:Cyclin B; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; C459801:MYCN protein, human; D008869:Microtubule-Associated Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D044786:S-Phase Kinase-Associated Proteins; D000077022:Survivin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases