Bidirectional on/off switch for controlled targeting of proteins to subcellular compartments

Kanwal, Charu; Mu, Sichun; Kern, Steven E.; Lim, Carol S.

doi:10.1016/j.jconrel.2004.05.008

Cited by 20 publications

(63 citation statements)

References 41 publications

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“…2) may indicate those women who may be susceptible to this or some forms of PR-dependent neoplasia. Cytoplasmic PR immunohistochemical staining has recently been reported in other epithelial and mesenchymal cell types (Taylor et al 2004;Ewies et al 2004) and to be mainly cytoplasmic when expressed in murine adenocarcinoma cells (Kanwal et al 2004). These data suggest the possibility that PR isoforms other than PR-B, PR-A and PR-S exist in normal and abnormal endometria.…”

Section: Discussionmentioning

confidence: 59%

Quantitative histomorphometric analysis of gonadal steroid receptor distribution in the normal human endometrium through the menstrual cycle

Taylor

Guzail

Wahab

et al. 2005

Histochem Cell Biol

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The aim of this study was to test the hypothesis that the distribution of oestrogen receptor beta (ERbeta) and androgen receptor (AR) are related to cell proliferation or correlated with the expression of progesterone receptor (PR) or oestrogen receptor alpha (ERalpha) in the normal human endometrium. Immunohistochemical distribution of immunoreactive ERbeta in well-characterised menstrual cycle biopsy samples was lowest in proliferative endometrial glands, highest in early secretory phase glands and maintained at approximately 20% throughout the rest of the menstrual cycle and was closely correlated with stromal AR and stromal ERbeta expression. Stromal ERbeta was not significantly altered until the menstrual phase of the cycle and was not correlated with the expression of any other antigen in the stroma or endometrial glands except stromal AR. By contrast, glandular AR immunoreactivity was below 5% early in the cycle, increased during the secretory phase and showed strong expression just before menstruation. PR and Ki-67 expression showed strong positive correlations, indicating that PR may be a potent regulator of endometrial proliferation. These data suggest that glandular ERbeta expression is closely associated with a functional secretory role whereas glandular ERalpha and PR are associated with proliferation; glandular AR expression may be the switch required for menstruation.

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Section: Discussionmentioning

confidence: 59%

Quantitative histomorphometric analysis of gonadal steroid receptor distribution in the normal human endometrium through the menstrual cycle

Taylor

Guzail

Wahab

et al. 2005

Histochem Cell Biol

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“…We have previously described a bidirectional protein switch whose subcellular localization is controlled by ligand (5). The protein switch consists of an NES, an NLS, and ligand binding domain (LBD).…”

Section: Using Signal Sequences For Therapymentioning

confidence: 99%

“…On the other hand, nuclear export signals (NESs) are leucine rich and can be used to direct proteins/ DNA to the cytoplasm of cells. For nuclear export signals, we have previously noted a leucine-rich Bconsensus^sequence of LX 1j3 LX 2j3 LXJ, where L = leu, X is any residue, and J = leu, val, or ile (5). However, since exceptions to this exist, this Bconsensus^may unnecessarily eliminate NESs that do not exactly fit this sequence.…”

Section: Introduction Signal Sequencesmentioning

confidence: 99%

Signal Sequences for Targeting of Gene Therapy Products to Subcellular Compartments: The Role Of CRM1 in Nucleocytoplasmic Shuttling of the Protein Switch

et al. 2007

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“…However, pharmacological approaches have limita-tions such as unanticipated off-targeting effects. 19,20 DMOG is a nonspecific prolyl hydroxylase inhibitor and questions remain concerning the specific mechanisms that produced the preconditioning effects we observed.…”

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confidence: 98%

Hypoxia Inducible Factor-1 Activation by Prolyl 4-Hydroxylase-2 Gene Silencing Attenuates Myocardial Ischemia Reperfusion Injury

Natarajan

Salloum

Fisher

et al. 2006

Circulation Research

153

115

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Abstract-Hypoxia inducible factor-1 (HIF-1) regulates changes in transcription of key genes such as inducible NO synthase (iNOS) in hypoxic/ischemic environments. In normoxia, HIF-1 activation is controlled by HIF-1␣-prolyl 4-hydroxylases, which target HIF-1␣ for ubiquitination and proteasomal degradation. We hypothesized that normoxic HIF-1 preservation could attenuate cardiac ischemia/reperfusion injury via a preconditioning effect. HIF-1 preservation was achieved by using small interfering RNA (siRNA) to silence murine HIF-1␣-prolyl-4 hydroxylase-2 (PHD2). PHD2 siRNA reduced PHD2 mRNA expression 89Ϯ1.5% (PϽ0.001) in a time-and concentration-dependent manner in normoxic murine microvascular endothelial cells (EC). PHD2 silencing in normoxic EC stabilized HIF-1␣ protein levels while significantly increasing HIF-1 transcriptional activity and iNOS mRNA expression. Wild-type mice infused with PHD2 siRNA (1.5 g/g body weight) showed a 61Ϯ2.4% (PϽ0.05) reduction in cardiac PHD2 mRNA within 24 hours. In addition HIF-1␣ protein levels and HIF-1-dependent iNOS mRNA levels were increased. PHD2 siRNA-transfected hearts from wild-type mice (nϭ6) subjected to 30 minutes ischemia followed by 60 minutes reperfusion exhibited reduced infarct size when compared with saline-treated controls (9.7Ϯ1.9% versus 31.6Ϯ1.8%, respectively, PϽ0.0001, nϭ6) and to control mice transfected with a nontargeting siRNA control (28.4Ϯ3.0%, PϽ0.0001, nϭ6). Hearts from iNOS knockout mice receiving PHD2 siRNA by identical injection protocol (nϭ6) exhibited infarct size indistinguishable from saline controls (28.7Ϯ1.3%). These results show that in vitro and in vivo, PHD2 silencing using a siRNA strategy produces transcriptionally active HIF-1. Key Words: small interfering RNA Ⅲ hypoxia inducible factor-1␣-prolyl 4-hydroxylase-2 Ⅲ cardiac ischemia/reperfusion Ⅲ inducible NO synthase H ypoxia inducible factor-1 (HIF-1) is a heterodimeric ␣,␤ transcription factor that mediates tissue responses to hypoxia. 1 HIF-1 promotes transcription of more than 40 genes involved in oxygen homeostasis in response to diminished oxygen tension, including inducible NO synthase (iNOS), vascular endothelial growth factor (VEGF), and heme oxygenase-1. 2 HIF-1␣ and -␤ mRNAs are expressed in most human tissues, 3 but HIF-1 activity is determined by expression and activity of the ␣ subunit. 4 Under normoxic conditions, HIF-1 is ubiquitinated and degraded by the 26S proteasome. [5][6][7] Posttranslational hydroxylation of HIF-1␣ targets the subunit for the von Hippel Lindau tumor suppressor protein E3 ubiquitin ligase complex. 8 -11 Three prolyl hydroxylase isoforms have been identified and use O 2 and 2-oxoglutarate as substrates to generate 4-hydroxyproline at residue 402 and/or 564 of HIF-1␣. 12,13 Because HIF-1␣-prolyl 4-hydroxylases possess a high Michaelis constant (K m ) for O 2 , changes in the cellular O 2 concentration are transduced into changes in the rate at which HIF-1␣ is hydroxylated, ubiquitinated, and degraded. 14 Expression of the prolyl 4-hydroxylases v...

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Bidirectional on/off switch for controlled targeting of proteins to subcellular compartments

Cited by 20 publications

References 41 publications

Quantitative histomorphometric analysis of gonadal steroid receptor distribution in the normal human endometrium through the menstrual cycle

Quantitative histomorphometric analysis of gonadal steroid receptor distribution in the normal human endometrium through the menstrual cycle

Signal Sequences for Targeting of Gene Therapy Products to Subcellular Compartments: The Role Of CRM1 in Nucleocytoplasmic Shuttling of the Protein Switch

Hypoxia Inducible Factor-1 Activation by Prolyl 4-Hydroxylase-2 Gene Silencing Attenuates Myocardial Ischemia Reperfusion Injury

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