Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer's disease-related insults

Tajima, Hiroto; Niikura, Takako; Hashimoto, Yuichi; Ito, Yuko; Kita, Yoshiko; Terashita, Kenzo; Yamazaki, Kazuto; Koto, Atsuo; Aiso, Sadakazu; Nishimoto, Ikuo

doi:10.1016/s0304-3940(02)00199-4

Cited by 131 publications

(144 citation statements)

References 8 publications

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“…The procedure involved synthesizing a library of RNA fragments from the nuclear RNA repertoire of a human melanoma line and selecting by affinity chromatography RNA fragments that bind to hPSF. The procedure yielded 5 such RNA fragments, 4 of which were mapped, by sequence identity, within 1 of the following genes: L1PA16, a non-LTR retroelement gene (8); MER11C, a LTR retroelement gene (9); MALAT-1, a noncoding gene (10,11); or HN, a mitochondrial gene coding for the peptide humanin (12); a fifth fragment, not shown in the figure, maps to a region that has not been characterized ( Fig. 1 and SI Text).…”

Section: Cloning and Mapping Human Rna Fragments That Bind To Hpsfmentioning

confidence: 99%

Role of human noncoding RNAs in the control of tumorigenesis

Feng

Lian

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

165

136

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Related studies showed that the protein PSF represses protooncogene transcription, and VL30 -1 RNA, a mouse noncoding retroelement RNA, binds and releases PSF from a proto-oncogene, activating transcription. Here we show that this mechanism regulates tumorigenesis in human cells, with human RNAs replacing VL30 -1 RNA. A library of human RNA fragments was used to isolate, by affinity chromatography, 5 noncoding RNA fragments that bind to human PSF (hPSF), releasing hPSF from a protooncogene and activating transcription. T he protein PSF (1) contains a DNA-binding domain (DBD) that binds to the regulatory region of a proto-oncogene and represses transcription, and 2 RNA-binding domains (RBDs) that bind VL30-1 RNA, releasing PSF from a repressed protooncogene and activating transcription (2-5). Mouse and human genomes encode homologous PSF proteins with Ϸ95% sequence identity, whereas the VL30-1 gene belongs to a family of mouse noncoding retroelement genes (6) that is not present in the human genome (7). To determine whether the PSF/RNA regulatory mechanism functions in human cells, a library of RNA fragments was constructed from the nuclear RNA repertoire of a human tumor cell, and the library was screened by affinity chromatography for RNAs that bind to human PSF (hPSF). The screen identified 5 hPSF-binding noncoding RNA fragments that release hPSF from a repressed proto-oncogene and activate transcription, similar to VL30-1 RNA. Each human RNA fragment maps to a matching sequence in a different human gene. The following experiments show that human hPSF-binding RNAs are involved in the control of tumorigenesis. Results Cloning and Mapping Human RNA Fragments That Bind to hPSFProtein. The finding that VL30-1 RNA, a mouse retroelement RNA that is not encoded in the human genome, binds selectively to hPSF protein and reverses repression of proto-oncogene transcription (2-5), prompted a search for human RNAs that have a similar function as VL30-1 RNA. The procedure involved synthesizing a library of RNA fragments from the nuclear RNA repertoire of a human melanoma line and selecting by affinity chromatography RNA fragments that bind to hPSF. The procedure yielded 5 such RNA fragments, 4 of which were mapped, by sequence identity, within 1 of the following genes: L1PA16, a non-LTR retroelement gene (8); MER11C, a LTR retroelement gene (9); MALAT-1, a noncoding gene (10, 11); or HN, a mitochondrial gene coding for the peptide humanin (12); a fifth fragment, not shown in the figure, maps to a region that has not been characterized ( Fig. 1 and SI Text).The sequence of the HN RNA fragment is 100% identical to a sequence in the mitochondrial 16S ribosomal RNA gene and is 85% identical to positions 21947595-21947823 on nuclear chromosome 17. Further testing showed that the HN RNA fragment is derived from the mitochondrial HN RNA and not from the nuclear RNA (SI Text). The mitochondrial HN RNA might be translocated to the nucleus or derived from a mitochondrial contamination in the nuclear preparation.Release of hPSF from ...

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Section: Cloning and Mapping Human Rna Fragments That Bind To Hpsfmentioning

confidence: 99%

Role of human noncoding RNAs in the control of tumorigenesis

Feng

Lian

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

165

136

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“…HN has been shown to be expressed in the testes of mice (15,17), and to confirm IGFBP-3-HN interaction in vivo, we immunoprecipitated mouse testis lysates with mouse-specific anti-IGFBP-3 antibody and control IgG. As shown in Fig.…”

Section: Confirmation Of Igfbp-3 and Hn Interactionmentioning

confidence: 99%

“…HN peptide has a distinct expression pattern during mouse development and in humans is specifically expressed in the AD brain. It is found in large intact neurons of the occipital lobe and in reactive glial cells in the hippocampus (17). Intracellular expression of HN is regulated in part by tripartite motif protein, TRIM11, through a ubiquitin-mediated protein degradation pathway (24).…”

Section: Cooperative Interaction Betweenmentioning

confidence: 99%

Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis

Ikonen

Liu²,

Hashimoto³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…A rabbit polyclonal anti-HN antibody (PO4) was described previously (Tajima et al, 2002). A rabbit polyclonal anti-ADNF antibody was raised against synthetic ADNF.…”

Section: Peptides and Materialsmentioning

confidence: 99%

Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease

Yamada

Chiba

Sasabe

et al. 2007

Neuropsychopharmacol

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Humanin (HN) and its derivatives, such as Colivelin (CLN), suppress neuronal death induced by insults related to Alzheimer's disease (AD) by activating STAT3 in vitro. They also ameliorate functional memory impairment of mice induced by anticholinergic drugs or soluble toxic amyloid-b (Ab) in vivo when either is directly administered into the cerebral ventricle or intraperitoneally injected. However, the mechanism underlying the in vivo effect remains uncharacterized. In addition, from the standpoint of clinical application, drug delivery methods that are less invasive and specific to the central nervous system (CNS) should be developed. In this study, we show that intranasally (i.n.) administered CLN can be successfully transferred to CNS via the olfactory bulb. Using several behavioral tests, we have demonstrated that i.n. administered CLN ameliorates memory impairment of AD models in a dose-responsive manner. Attenuation of AD-related memory impairment by HN derivatives such as CLN appears to be correlated with an increase in STAT3 phosphorylation levels in the septohippocampal region, suggesting that anti-AD activities of HN derivatives may be mediated by activation of STAT3 in vivo as they are in vitro. We further demonstrate that CLN treatment inhibits an Ab induced decrease in the number of choline acetyltransferase (ChAT)-positive neurons in the medial septum. Combined with the finding that HN derivatives upregulate mRNA expression of neuronal ChAT and vesicular acetylcholine transporter (VAChT) in vitro, it is assumed that CLN may ameliorate memory impairment of AD models by supporting cholinergic neurotransmission, which is at least partly mediated by STAT3-mediated transcriptional upregulation of ChAT and VAChT.

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Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer's disease-related insults

Cited by 131 publications

References 8 publications

Role of human noncoding RNAs in the control of tumorigenesis

Role of human noncoding RNAs in the control of tumorigenesis

Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis

Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease

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