Enhanced microtubule-dependent trafficking and p53 nuclear accumulation by suppression of microtubule dynamics.
The tumor suppressor protein p53 localizes to microtubules (MT) and, in response to DNA damage, is transported to the nucleus via the MT minus-end-directed motor protein dynein. Dynein is also responsible for MT-mediated nuclear targeting of adenovirus type 2 (Ad2). Here we show that treatment with low concentrations of MT-targeting compounds (MTCs) that do not disrupt the MT network but are known to suppress MT dynamics enhanced p53 nuclear accumulation, and the activation of the p53-downstream target genes. p53 nuclear accumulation required binding of MTCs to MTs and enhanced the induction of p53-up-regulated modulator of apoptosis (PUMA) mRNA and apoptosis on challenging cells with the DNA-damaging drug adriamycin. Low concentrations of MTCs enhanced the rate of movement of fluorescent Ad2 to the nucleus and increased the nuclear targeting efficiency of Ad2. We propose that suppression of MT dynamics by low concentrations of MTCs enhances MT-dependent trafficking toward the minus ends of MTs and facilitates nuclear targeting.
Giannakakou
Paraskevi
P
Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. paraskevi_giannakakou@emory.org
Nakano
Michel
M
Nicolaou
Kyriacos C
KC
O'Brate
Aurora
A
Yu
Jian
J
Blagosklonny
Mikhail V
MV
Greber
Urs F
UF
Fojo
Tito
T
D000260:Adenoviruses, Human / Q000378:metabolism; D017209:Apoptosis; D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism*; D003078:Colchicine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D034261:Epothilones; D006367:HeLa Cells; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D015739:Nocodazole / Q000494:pharmacology; D009687:Nuclear Proteins; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D015533:Transcriptional Activation / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014750:Vincristine / Q000378:metabolism / Q000494:pharmacology
D034261:Epothilones; D018942:Macrolides; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; C093787:epothilone A; D014750:Vincristine; D004317:Doxorubicin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D017239:Paclitaxel; D015739:Nocodazole; D003078:Colchicine; C093788:epothilone B