Signals mediating nuclear targeting and their regulation: Application in drug delivery

Jans, David A.; Chan, Chee Kai; Huebner, Sebastian

doi:10.1002/(sici)1098-1128(199807)18:4<189::aid-med1>3.0.co;2-r

Cited by 73 publications

(19 citation statements)

References 275 publications

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“…Different classes of NLS sequences exist (70), which are divided into classical and nonclassical sequences. The classical NLS sequences are characterized by a stretch of basic, charged amino acids.…”

Section: Nuclear Localization Signalsmentioning

confidence: 99%

“…These NLSs interact with the importin !/ importin " heterodimer to facilitate nuclear import of their protein cargo (72). Some other NLSs can be recognized by importin " alone (70). These sequences resemble the IBB domain from importin !.…”

Section: Nuclear Localization Signalsmentioning

confidence: 99%

“…In contrast to classical NLS sequences that exclusively mediate nuclear import, the M9 NLS sequences also contain a nuclear export signal (NES). NESs are largely hydrophobic leucine-rich sequences that have been identified in several proteins (70,76).…”

Section: Nuclear Localization Signalsmentioning

confidence: 99%

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The Nuclear Pore Complex: The Gateway to Successful Nonviral Gene Delivery

et al. 2006

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One of the limiting steps in the efficiency of nonviral gene delivery is transport of genetic material across the nuclear membrane. Trafficking of nuclear proteins from the cytoplasm into the nucleus occurs via the nuclear pore complex and is mediated by nuclear localization signals and their nuclear receptors. Several strategies employing this transport mechanism have been designed and explored to improve nonviral gene delivery. In this article, we review the mechanism of nuclear import through the nuclear pore complex and the strategies used to facilitate nuclear import of exogenous DNA and improve gene expression.

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Section: Nuclear Localization Signalsmentioning

confidence: 99%

Section: Nuclear Localization Signalsmentioning

confidence: 99%

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The Nuclear Pore Complex: The Gateway to Successful Nonviral Gene Delivery

et al. 2006

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“…Similarly, the M9 shuttling (import/ export) signal sequence attached to cationic peptides have been used as a delivery system for plasmid DNA (67). An excellent review summarizes the nuclear import, export, and shuttling signals, and their application to drug delivery (68). In all of the examples mentioned here, signals have been used unidirectionally to target a drugVbe it an oligonucleotide, polymer or plasmidVto a final compartment.…”

Section: Import Export and Other Signals: Application To Drug Deliverymentioning

confidence: 99%

“…NLSs and NESs have routinely been added onto proteins to enhance or modify their cellular destination; for an excellent review see Jans et al (68). The main disadvantage with adding proteins with NLSs/NESs is that the patient still expresses the mislocalized protein, and in some cases, the mislocalized protein exhibits a dominant effect over the non-mislocalized protein (93).…”

Section: Enhancing Import or Export Of Proteinsmentioning

confidence: 99%

Controlling Protein Compartmentalization to Overcome Disease

2006

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Over the past decade, considerable progress has been made to improve our understanding of the intracellular transport of proteins. Mechanisms of nuclear import and export involving classical receptors have been studied. Signal sequences required for directing a protein molecule to a specific cellular compartment have been defined. Knowledge of subcellular trafficking of proteins has also increased our understanding of diseases caused due to mislocalization of proteins. A specific protein on deviating from its native cellular compartment may result in disease due to loss of its normal functioning and aberrant activity in the "wrong" compartment. Mislocalization of proteins results in diseases that range from metabolic disorders to cancer. In this review we discuss some of the diseases caused due to mislocalization. We further focus on application of nucleocytoplasmic transport to drug delivery. Various rationales to treat diseases by exploiting intracellular transport machinery have been proposed. Although the pathways for intracellular movement of proteins have been defined, these have not been adequately utilized for management of diseases involving mislocalized proteins. This review stresses the need for designing drug delivery systems utilizing these mechanisms as this area is least exploited but offers great potential.

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Nuclear targeting signal recognition: a key control point in nuclear transport?

2000

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Recent progress indicates that there are multiple pathways of nucleocytoplasmic transport which involve specific targeting sequences, such as nuclear localization sequences (NLSs), and cytosolic receptor molecules of the importin/karyopherin superfamily which recognise and dock the NLS‐containing proteins at the nuclear pore. This first step of nuclear import/export is of central importance, with the affinity of the importin‐targeting sequence interaction a critical parameter in determining transport efficiency. Different importins possess distinct NLS‐binding specificities, which allows the system to be modulated through differential expression of the importins themselves, as well as through competition between different importins for the same protein, and between different proteins for the same importin. The targeting sequence‐importin interaction can also be influenced directly by phosphorylation increasing the affinity of the interaction with importins or by targeting sequence masking through phosphorylation or specific protein binding. Targeting sequence recognition thus appears to represent a key control point in the regulation of nuclear transport. BioEssays 22:532–544, 2000. © 2000 John Wiley & Sons, Inc.

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Signals mediating nuclear targeting and their regulation: Application in drug delivery

Cited by 73 publications

References 275 publications

The Nuclear Pore Complex: The Gateway to Successful Nonviral Gene Delivery

The Nuclear Pore Complex: The Gateway to Successful Nonviral Gene Delivery

Controlling Protein Compartmentalization to Overcome Disease

Nuclear targeting signal recognition: a key control point in nuclear transport?

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