Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes

被引：97

作者：

Chiefari, Eusebio ^{[1
]}

Iiritano, Stefania ^{[1
]}

Paonessa, Francesco ^{[1
]}

Le Pera, Ilaria ^{[1
]}

Arcidiacono, Biagio ^{[1
]}

Filocamo, Mirella ^{[2
]}

Foti, Daniela ^{[1
]}

Liebhaber, Stephen A. ^{[3
]}

Brunetti, Antonio ^{[1
,4
]}

机构：

[1] Univ Catanzaro Magna Graecia, Dipartimento Med Sperimentale & Clin G Salvatore, I-88100 Catanzaro, Italy

[2] Ist Giannina Gaslini, Lab Diagnosi Prepostnatale Malattie Metab, I-16147 Genoa, Italy

[3] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA

[4] Univ Catanzaro Magna Graecia, Cattedra Endocrinol, I-88100 Catanzaro, Italy

来源：

NATURE COMMUNICATIONS | 2010年 / 1卷

关键词：

MESSENGER-RNA STABILITY; POLY(C)-BINDING PROTEINS; PROCESSED PSEUDOGENES; MOUSE OOCYTES; RECEPTOR GENE; HUMAN GENOME; CODING GENE; EXPRESSION; IDENTIFICATION; TRANSCRIPTION;

D O I：

10.1038/ncomms1040

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Processed pseudogenes are non-functional copies of normal genes that arise by a process of mRNA retrotransposition. The human genome contains thousands of pseudogenes; however, knowledge regarding their biological role is limited. Previously, we demonstrated that high mobility group A1 (HMGA1) protein regulates the insulin receptor (INSR) gene and that two diabetic patients demonstrated a marked destabilization of HMGA1 mRNA. In this paper we report that this destabilization of HMGA1 mRNA is triggered by enhanced expression of RNA from an HMGA1 pseudogene, HMGA1-p. Targeted knockdown of HMGA1-p mRNA in patient cells results in a reciprocal increase in HMGA1 mRNA stability and expression levels with a parallel correction in cell-surface INSR expression and insulin binding. These data provide evidence for a regulatory role of an expressed pseudogene in humans and establishes a novel mechanistic linkage between pseudogene HMGA1-p expression and type 2 diabetes mellitus.

引用

页数：7

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