Impaired expression of importin/karyopherin β1 leads to post-implantation lethality

Miura, Katsutaka; Yoshinobu, Kumiko; Imaizumi, Tsutomu; Haruna, Kyoko; Miyamoto, Yoichi; Yoneda, Yoshihiro; Nakagata, Naomi; Araki, Masatake; Miyakawa, Taihei; Yamamura, Ken Ichi; Araki, Kimi

doi:10.1016/j.bbrc.2005.12.151

Cited by 15 publications

(7 citation statements)

References 24 publications

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“…The highly specific effects of long 3′UTR targeting of importin β1 are all the more remarkable given its central roles in nuclear import (Chook and Suel, 2011; Harel and Forbes, 2004), and the fact that a complete knockout is lethal very early in embryogenesis, already at the blast ocyst stage (Miura et al, 2006). The pleiotropy and critical importance of importin β1 pose a significant challenge for dissecting its specific functions (Soderholm et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Local translation may also allow separation of cytoplasmic transport functions from the nucleocytoplasmic transport roles of importin β1, which include enhancing the affinity of its importin α partners for nuclear localization sequences (NLS) within a cargo protein, and facilitating transport through the nuclear pore (Chook and Suel, 2011; Harel and Forbes, 2004). The essential role of importin β1 in these fundamental cellular processes was highlighted by blastocyst stage lethality in homozygous embryos from a gene trap importin β1 mouse line (Miura et al, 2006). Thus, although targeting of importin β1 in axons would provide a stringent test of the validity of local axonal translation and the contribution of importins to retrograde injury signaling and other distal cytoplasmic functions, such targeting requires separation of cytoplasmic functions of importins from their essential housekeeping roles in nucleocytoplasmic transport in cell bodies.…”

Section: Introductionmentioning

confidence: 99%

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Subcellular Knockout of Importin β1 Perturbs Axonal Retrograde Signaling

Perry

Doron-Mandel

Iavnilovitch

et al. 2012

Neuron

163

174

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Summary Subcellular localization of mRNA enables compartmentalized regulation within large cells. Neurons are the longest known cells, however so far evidence is lacking for an essential role of endogenous mRNA localization in axons. Localized upregulation of importin β1 in lesioned axons coordinates a retrograde injury signaling complex transported to the neuronal cell body. Here we show that a long 3′ untranslated region (3′UTR) directs axonal localization of importin β1. Conditional targeting of this 3′UTR region in mice causes subcellular loss of importin β1 mRNA and protein in axons, without affecting cell body levels or nuclear functions in sensory neurons. Strikingly, axonal knockout of importin β1 attenuates cell body transcriptional responses to nerve injury and delays functional recovery in vivo. Thus, localized translation of importin β1 mRNA enables separation of cytoplasmic and nuclear transport functions of importins, and is required for efficient retrograde signaling in injured axons.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Subcellular Knockout of Importin β1 Perturbs Axonal Retrograde Signaling

Perry

Doron-Mandel

Iavnilovitch

et al. 2012

Neuron

163

174

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“…We therefore cannot exclude the possibility that abnormalities observed in Pcnt ocd/ocd mice reflect the altered expression of the overlapping gene. It has been reported that integration of the trap vector into the promoter region in reverse orientation generated a hypomorphic allele of the Kpnb1 gene (26).…”

Section: Discussionmentioning

confidence: 99%

Pericentrin, a centrosomal protein related to microcephalic primordial dwarfism, is required for olfactory cilia assembly in mice

et al. 2009

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The Drosophila pericentrin-like protein has been shown to be essential for the formation of the sensory cilia of chemosensory and mechanosensory neurons by mutant analysis in flies, while the in vivo function of pericentrin, a well-studied mammalian centrosomal protein related to microcephalic primordial dwarfism, has been unclear. To determine whether pericentrin is required for ciliogenesis in mammals, we generated and analyzed mice with a hypomorphic mutation of Pcnt encoding the mouse pericentrin. Immunofluorescence analysis demonstrated that olfactory cilia of chemosensory neurons in the nasal olfactory epithelium were malformed in the homozygous mutant mice. On the other hand, the assembly of motile and primary cilia of non-neuronal epithelial cells and the formation of sperm flagella were not affected in the Pcnt-mutant mice. The defective assembly of olfactory cilia in the mutant was apparent from birth. The mutant animals displayed reduced olfactory performance in agreement with the compromised assembly of olfactory cilia. Our findings suggest that pericentrin is essential for the assembly of chemosensory cilia of olfactory receptor neurons, but it is not globally required for cilia formation in mammals.

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“…Importin β1 (Impβ1) is an important member of the Importin family of nuclear transporters that is highly expressed in transformed cells such as in Simian Virus 40 (SV40) large T-antigen-mediated transformation, Human Papillomavirus-16 (HPV-16) E6/E7-transformed epithelial cells and in gastric, bladder, breast and cervical cancer cell lines [2][3][4][5]. Highly conserved in mammals, and ubiquitously expressed in human tissues and cells, Impβ1 is critical for early embryonic development in the mouse, worm and fly [6,7] because of key roles in both interphase and mitosis [8]. Through its ability to mediate interaction of transport complexes with the nucleoporin (Nup) proteins of the nuclear pore complex (NPC), Impβ1 mediates nuclear import during interphase of a range of different proteins, including of cargoes bound directly to Impβ1 such as the signalling molecule parathyroid hormone-related protein PTHrP [9], cyclin B1 [10], chromatin remodelling factors such as SOX9 [11] and SRY [12] and basic loop helix factors such as activator protein-1 AP-1 and cAMP-response element-binding protein CREB [13].…”

Section: Introductionmentioning

confidence: 99%

Hyper-dependence of breast cancer cell types on the nuclear transporter Importin β1

Kuusisto

Jans

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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We previously reported that overexpression of members of the Importin (Imp) superfamily of nuclear transporters results in increased nuclear trafficking through conventional transport pathways in tumour cells. Here we show for the first time that the extent of overexpression of Impβ1 correlates with disease state in the MCF10 human breast tumour progression system. Excitingly, we find that targeting Impβ1 activity through siRNA is >30 times more efficient in decreasing the viability of malignant ductal carcinoma cells compared to isogenic non-transformed counterparts, and is highly potent and tumour selective at subnanomolar concentrations. Tumour cell selectivity of the siRNA effects was unique to Impβ1 and not other Imps, with flow cytometric analysis showing >60% increased cell death compared to controls concomitant with reduced nuclear import efficiency as indicated by confocal microscopic analysis. This hypersensitivity of malignant cell types to Impβ1 knockdown raises the exciting possibility of anti-cancer therapies targeted at Impβ1.

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Impaired expression of importin/karyopherin β1 leads to post-implantation lethality

Cited by 15 publications

References 24 publications

Subcellular Knockout of Importin β1 Perturbs Axonal Retrograde Signaling

Subcellular Knockout of Importin β1 Perturbs Axonal Retrograde Signaling

Pericentrin, a centrosomal protein related to microcephalic primordial dwarfism, is required for olfactory cilia assembly in mice

Hyper-dependence of breast cancer cell types on the nuclear transporter Importin β1

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