Abstract:
:Cancer cells acquire resistance to DNA-damaging therapeutic agents, such as cisplatin, but the genetic mechanisms through which this occurs remain unclear. We show that the c-MYC oncoprotein increases cisplatin resistance by decreasing production of the c-MYC inhibitor BIN1 (bridging integrator 1). The sensitivity of cancer cells to cisplatin depended on BIN1 abundance, regardless of the p53 gene status. BIN1 bound to the automodification domain of and suppressed the catalytic activity of poly(ADP-ribose) polymerase 1 (PARP1, EC 2.4.2.30), an enzyme essential for DNA repair, thereby reducing the stability of the genome. The inhibition of PARP1 activity was sufficient for BIN1 to suppress c-MYC-mediated transactivation, the G(2)-M transition, and cisplatin resistance. Conversely, overexpressed c-MYC repressed BIN1 expression by blocking its activation by the MYC-interacting zinc finger transcription factor 1 (MIZ1) and thereby released PARP1 activity. Thus, a c-MYC-mediated positive feedback loop may contribute to cancer cell resistance to cisplatin.
journal_name
Sci Signaljournal_title
Science signalingauthors
Pyndiah S,Tanida S,Ahmed KM,Cassimere EK,Choe C,Sakamuro Ddoi
10.1126/scisignal.2001556subject
Has Abstractpub_date
2011-03-29 00:00:00pages
ra19issue
166eissn
1945-0877issn
1937-9145pii
4/166/ra19journal_volume
4pub_type
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