IGF2 mRNA-binding protein 2: biological function and putative role in type 2 diabetes

Recent genome-wide association (GWA) studies of type 2 diabetes (T2D) have implicated IGF2 mRNA-binding protein 2 (IMP2/IGF2BP2) as one of the several factors in the etiology of late onset diabetes. IMP2 belongs to a family of oncofetal mRNA-binding proteins implicated in RNA localization, stability, and translation that are essential for normal embryonic growth and development. This review provides a background to the IMP protein family with an emphasis on human IMP2, followed by a closer look at the GWA studies to evaluate the significance, if any, of the proposed correlation between IMP2 and T2D.

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Insulin-like growth factor 2 mRNA-binding protein 2 – a potential link between type 2 diabetes mellitus and cancer

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab391 ◽

2021 ◽

Author(s):

Junguo Cao ◽

Weijia Yan ◽

Xiujian Ma ◽

Haiyan Huang ◽

Hong Yan

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Insulin Sensitivity ◽

Growth Factor ◽

Splice Variant ◽

Binding Protein ◽

Mrna Binding Protein ◽

Mrna Binding

Abstract Context Type 2 diabetes mellitus (T2DM) and cancer share a variety of risk factors and pathophysiological features. It is becoming increasingly accepted that the two diseases are related, and that T2DM increases the risk of certain malignancies. This review summarizes recent advancements in the elucidation of functions of insulin-like growth factor 2 (IGF-2) mRNA-binding protein 2 (IGF2BP2) in T2DM and cancer. Evidence Acquisition A PubMed review of the literature was conducted, and search terms included: IGF2BP2, IMP2, or p62 in combination with cancer or T2DM. Additional sources were identified through manual searches of reference lists. Evidence Synthesis The increased risk of multiple malignancies and cancer-associated mortality in patients with T2DM is believed to be driven by insulin resistance, hyperinsulinemia, hyperglycemia, chronic inflammation, and dysregulation of adipokines and sex hormones. Furthermore, IGF-2 is oncogenic, and its loss-of-function splice variant is protective against T2DM, which highlights the pivotal role of this growth factor in the pathogenesis of these two diseases. IGF-2 mRNA-binding proteins, particularly IGF2BP2, are also involved in T2DM and cancer, and single nucleotide polymorphisms of IGF2BP2 are associated with both diseases. Deletion of the IGF2BP2 gene in mice improves their glucose tolerance and insulin sensitivity and mice with transgenic p62, a splice variant of IGF2BP2, are prone to diet-induced fatty liver disease and hepatocellular carcinoma, suggesting the biological significance of IGF2BP2 in T2DM and cancer. Conclusions Accumulating evidence revealed that IGF2BP2 mediates the pathogenesis of T2DM and cancer by regulating glucose metabolism, insulin sensitivity, and tumorigenesis. This review provides insight into the potential involvement of this RNA binding protein in the link between T2DM and cancer.

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Regulation of Neuroendocrine Plasticity by the RNA-Binding Protein ZFP36L1

10.1101/2021.10.22.465501 ◽

2021 ◽

Author(s):

Hsiao-Yun Chen ◽

Yavuz T. Durmaz ◽

Yixiang Li ◽

Amin H. Sabet ◽

Amir Vajdi ◽

...

Keyword(s):

Transcription Factors ◽

Rna Binding ◽

Binding Protein ◽

Neuroendocrine Differentiation ◽

Loss Of Function ◽

Lung Cancers ◽

Genome Wide ◽

Mrna Binding Protein ◽

Inflammatory Phenotype ◽

Mrna Binding

Some small cell lung cancers (SCLCs) are highly sensitive to inhibitors of the histone demethylase LSD1. LSD1 inhibitors are thought to induce their anti-proliferative effects by blocking neuroendocrine differentiation, but the mechanisms by which LSD1 controls the SCLC neuroendocrine phenotype are not well understood. To identify genes required for LSD1 inhibitor sensitivity in SCLC, we performed a positive selection genome-wide CRISPR/Cas9 loss of function screen and found that ZFP36L1, an mRNA-binding protein that destabilizes mRNAs, is required for LSD1 inhibitor sensitivity. LSD1 binds and represses ZFP36L1 and upon LSD1 inhibition, ZFP36L1 expression is restored, which is sufficient to block the SCLC neuroendocrine differentiation phenotype and induce a non-neuroendocrine inflammatory phenotype. Mechanistically, ZFP36L1 binds and destabilizes SOX2 and INSM1 mRNAs, two transcription factors that are required for SCLC neuroendocrine differentiation. This work identifies ZFP36L1 as an LSD1 target gene that controls the SCLC neuroendocrine phenotype and demonstrates that modulating mRNA stability of lineage transcription factors controls neuroendocrine to non-neuroendocrine plasticity.

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Gene Variants for Obesity and Type 2 Diabetes – A Shared Aetiology?

European Endocrinology ◽

10.17925/ee.2009.05.00.27 ◽

2009 ◽

Vol 05 (0) ◽

pp. 27

Author(s):

Clara C Elbers ◽

Marcel GM Wolfs ◽

Timon W van Haeften ◽

◽

...

Keyword(s):

Type 2 Diabetes ◽

Molecular Mechanisms ◽

Susceptibility Loci ◽

Genetic Traits ◽

Genome Wide ◽

Alternative Approaches ◽

Diabetes And Obesity ◽

Gwa Studies

The incidence of type 2 diabetes is rising rapidly worldwide, mainly due to the increase in the incidence of obesity. Both obesity and type 2 diabetes are complex genetic traits, but they share some non-genetic risk factors. Hence, it is tempting to speculate that susceptibility to type 2 diabetes and obesity may also involve shared underlying genetic factors acting on common molecular mechanisms. Recent genome-wide association (GWA) studies identified 17 common loci for obesity and 19 common loci for type 2 diabetes. This article explores whether the susceptibility loci for type 2 diabetes and obesity can indicate potential overlapping mechanisms in the disorders. In addition, we touch on the challenges regarding follow-up of confirmed GWA signals, as well as alternative approaches to analysing GWA data to a fuller potential.

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