p53 is associated with cellular microtubules and is transported to the nucleus by dynein

Abstract

Here we show that p53 protein is physically associated with tubulin in vivo and in vitro, and that it localizes to cellular microtubules. Treatment with vincristine or paclitaxel before DNA-damage or before leptomycin B treatment reduces nuclear accumulation of p53 and expression of mdm2 and p21. Overexpression of dynamitin or microinjection of anti-dynein antibody before DNA damage abrogates nuclear accumulation of p53. Our results indicate that transport of p53 along microtubules is dynein-dependent. The first 25 amino acids of p53 contain the residues that are essential for binding to microtubules. We propose that functional microtubules and the dynein motor protein participate in transport of p53 and facilitate its accumulation in the nucleus after DNA damage.

Kinetic stabilization of microtubule dynamic instability by benomyl increases the nuclear transport of p53

“…As reported earlier [24,44], p53 was found to be associated with microtubules in both the cells that were lysed without formaldehyde treatment (Fig. 7B, lanes 1-3) and after formaldehyde treatment for 1 h (Fig.…”

“…In contrast, low concentration of benomyl caused a strong increase in the nuclear localization of p53 in the presence of cisplatin. Although p53 is shown to be transported into the nucleus through the dynein/dynamitin complex [23,24], it can bind to microtubules directly and it was shown to bind preferentially to polymerized microtubules than to tubulin dimers [24]. Therefore, it is quite possible that the binding of p53 to the stabilized microtubules in the presence of low concentration of benomyl might prevent its degradation; however, its transport into the nucleus needs the dynein/ dynamitin motor complex [23,24].…”

“…Kinetic suppression of microtubule dynamics increased the association of DLC with microtubules Since p53 is reported to be transported into the nucleus through the microtubular tracks by the dynein/dynamitin motor complex [23,24], we examined the localization of the motor protein DLC on microtubules under normal conditions and under the suppressed dynamic instability conditions using EGFP transfected MCF-7 cells and confocal microscopy.…”

“…Microtubule targeted agents have also been shown to alter the expression [21] and translocation of the tumor suppressor protein, p53 into the nucleus [22,23] suggesting that the nuclear accumulation of p53 is linked with the assembly dynamics of microtubules. Further, the translocation of p53 into the nucleus is thought to occur through the microtubule tracks [22][23][24] and low concentration of microtubule targeted drugs is shown to increase the nuclear accumulation of p53 [22].…”

Drug resistance associated with loss of p53 involves extensive alterations in microtubule composition and dynamics

“…We recently reported that chemoresistance present in p53-deficient cells might be attributed to defective apoptotic pathways (Galmarini et al, 2001). However, p53 also associates with microtubules in vitro and in vivo (Giannakakou et al, 2000b), and has been reported to regulate negatively the putative microtubule-stabilising protein microtubule-associated protein 4 (MAP4), the microtubule-related inhibitor of apoptosis survivin (Mirza et al, 2002), and the microtubule-destabilising protein stathmin/OP18 (Johnsen et al, 2000;Murphy et al, 1999). Whether these interactions of p53 with the microtubule network directly affect microtubule composition and dynamics thus favouring drug resistance is not known.…”