A microtubule-facilitated nuclear import pathway for cancer regulatory proteins

Daniela Martino Roth, Gregory William Moseley, Dominic Glover, Colin William Pouton, David Andrew Jans

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Nuclear protein import is dependent on specific targeting signals within cargo proteins recognized by importins (IMPs) that mediate translocation through the nuclear pore. Recent evidence, however, implicates a role for the microtubule (MT) network in facilitating nuclear import of the cancer regulatory proteins parathyroid hormone-related protein (PTHrP) and p53 tumor suppressor. Here we assess the extent to which MT and actin integrity may be generally required for nuclear protein import for the first time. We examine 10 nuclear-localizing proteins with diverse IMP-dependent nuclear import pathways, our results indicating that the cytoskeleton does not have a general mechanistic role in nuclear localization sequence-dependent nuclear protein import. Of the proteins examined, only the p110(Rb) tumor suppressor protein Rb, together with p53 and PTHrP, was found to require MT integrity for optimal nuclear import. Fluorescence recovery after photobleaching experiments indicated that the MT-dependent nuclear transport pathway increases both the rate and extent of Rb nuclear import but does not affect Rb nuclear export. Dynamitin overexpression experiments implicate the MT motor dynein in the import process. The results indicate that, additional to IMP/diffusion-dependent processes, certain cancer regulatory proteins utilize an MT-enhanced pathway for accelerated nuclear import that is presumably required for their nuclear functions.
Original languageEnglish
Pages (from-to)673-686
Number of pages14
JournalTraffic
Volume8
Issue number6
DOIs
Publication statusPublished - 2007

Keywords

  • Active Transport, Cell Nucleus Animals COS Cells Cell Line, Tumor Cercopithecus aethiops Humans Karyopherins/*metabolism Microtubules/*metabolism Parathyroid Hormone-Related Protein/*metabolism Retinoblastoma Protein/*metabolism Tumor Suppressor Protein p53/*metabolism

Cite this

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title = "A microtubule-facilitated nuclear import pathway for cancer regulatory proteins",
abstract = "Nuclear protein import is dependent on specific targeting signals within cargo proteins recognized by importins (IMPs) that mediate translocation through the nuclear pore. Recent evidence, however, implicates a role for the microtubule (MT) network in facilitating nuclear import of the cancer regulatory proteins parathyroid hormone-related protein (PTHrP) and p53 tumor suppressor. Here we assess the extent to which MT and actin integrity may be generally required for nuclear protein import for the first time. We examine 10 nuclear-localizing proteins with diverse IMP-dependent nuclear import pathways, our results indicating that the cytoskeleton does not have a general mechanistic role in nuclear localization sequence-dependent nuclear protein import. Of the proteins examined, only the p110(Rb) tumor suppressor protein Rb, together with p53 and PTHrP, was found to require MT integrity for optimal nuclear import. Fluorescence recovery after photobleaching experiments indicated that the MT-dependent nuclear transport pathway increases both the rate and extent of Rb nuclear import but does not affect Rb nuclear export. Dynamitin overexpression experiments implicate the MT motor dynein in the import process. The results indicate that, additional to IMP/diffusion-dependent processes, certain cancer regulatory proteins utilize an MT-enhanced pathway for accelerated nuclear import that is presumably required for their nuclear functions.",
keywords = "Active Transport, Cell Nucleus Animals COS Cells Cell Line, Tumor Cercopithecus aethiops Humans Karyopherins/*metabolism Microtubules/*metabolism Parathyroid Hormone-Related Protein/*metabolism Retinoblastoma Protein/*metabolism Tumor Suppressor Protein p53/*metabolism",
author = "{Martino Roth}, Daniela and Moseley, {Gregory William} and Dominic Glover and Pouton, {Colin William} and Jans, {David Andrew}",
note = "M1 - 6 Roth, Daniela Martino Moseley, Gregory W Glover, Dominic Pouton, Colin W Jans, David A eng Research Support, Non-U.S. Gov't Denmark Copenhagen, Denmark 2007/05/22 09:00 Traffic. 2007 Jun;8(6):673-86.",
year = "2007",
doi = "10.1111/j.1600-0854.2007.00564.x",
language = "English",
volume = "8",
pages = "673--686",
journal = "Traffic",
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A microtubule-facilitated nuclear import pathway for cancer regulatory proteins. / Martino Roth, Daniela; Moseley, Gregory William; Glover, Dominic; Pouton, Colin William; Jans, David Andrew.

In: Traffic, Vol. 8, No. 6, 2007, p. 673-686.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A microtubule-facilitated nuclear import pathway for cancer regulatory proteins

AU - Martino Roth, Daniela

AU - Moseley, Gregory William

AU - Glover, Dominic

AU - Pouton, Colin William

AU - Jans, David Andrew

N1 - M1 - 6 Roth, Daniela Martino Moseley, Gregory W Glover, Dominic Pouton, Colin W Jans, David A eng Research Support, Non-U.S. Gov't Denmark Copenhagen, Denmark 2007/05/22 09:00 Traffic. 2007 Jun;8(6):673-86.

PY - 2007

Y1 - 2007

N2 - Nuclear protein import is dependent on specific targeting signals within cargo proteins recognized by importins (IMPs) that mediate translocation through the nuclear pore. Recent evidence, however, implicates a role for the microtubule (MT) network in facilitating nuclear import of the cancer regulatory proteins parathyroid hormone-related protein (PTHrP) and p53 tumor suppressor. Here we assess the extent to which MT and actin integrity may be generally required for nuclear protein import for the first time. We examine 10 nuclear-localizing proteins with diverse IMP-dependent nuclear import pathways, our results indicating that the cytoskeleton does not have a general mechanistic role in nuclear localization sequence-dependent nuclear protein import. Of the proteins examined, only the p110(Rb) tumor suppressor protein Rb, together with p53 and PTHrP, was found to require MT integrity for optimal nuclear import. Fluorescence recovery after photobleaching experiments indicated that the MT-dependent nuclear transport pathway increases both the rate and extent of Rb nuclear import but does not affect Rb nuclear export. Dynamitin overexpression experiments implicate the MT motor dynein in the import process. The results indicate that, additional to IMP/diffusion-dependent processes, certain cancer regulatory proteins utilize an MT-enhanced pathway for accelerated nuclear import that is presumably required for their nuclear functions.

AB - Nuclear protein import is dependent on specific targeting signals within cargo proteins recognized by importins (IMPs) that mediate translocation through the nuclear pore. Recent evidence, however, implicates a role for the microtubule (MT) network in facilitating nuclear import of the cancer regulatory proteins parathyroid hormone-related protein (PTHrP) and p53 tumor suppressor. Here we assess the extent to which MT and actin integrity may be generally required for nuclear protein import for the first time. We examine 10 nuclear-localizing proteins with diverse IMP-dependent nuclear import pathways, our results indicating that the cytoskeleton does not have a general mechanistic role in nuclear localization sequence-dependent nuclear protein import. Of the proteins examined, only the p110(Rb) tumor suppressor protein Rb, together with p53 and PTHrP, was found to require MT integrity for optimal nuclear import. Fluorescence recovery after photobleaching experiments indicated that the MT-dependent nuclear transport pathway increases both the rate and extent of Rb nuclear import but does not affect Rb nuclear export. Dynamitin overexpression experiments implicate the MT motor dynein in the import process. The results indicate that, additional to IMP/diffusion-dependent processes, certain cancer regulatory proteins utilize an MT-enhanced pathway for accelerated nuclear import that is presumably required for their nuclear functions.

KW - Active Transport, Cell Nucleus Animals COS Cells Cell Line, Tumor Cercopithecus aethiops Humans Karyopherins/metabolism Microtubules/metabolism Parathyroid Hormone-Related Protein/metabolism Retinoblastoma Protein/metabolism Tumor Suppressor Protein p53/m

UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17511743

U2 - 10.1111/j.1600-0854.2007.00564.x

DO - 10.1111/j.1600-0854.2007.00564.x

M3 - Article

VL - 8

SP - 673

EP - 686

JO - Traffic

JF - Traffic

SN - 1398-9219

IS - 6

ER -