RNA binding protein IGF2BP2 expression is induced by stress in the heart and mediates dilated cardiomyopathy.

The IGF2BP family of RNA binding proteins consists of three paralogs that regulate intracellular RNA localization, RNA stability, and translational control. Although IGF2BP1 and 3 are oncofetal proteins, IGF2BP2 expression is maintained in many tissues, including the heart, into adulthood. IGF2BP2 is upregulated in cardiomyocytes during cardiac stress and remodeling and returns to normal levels in recovering hearts. We wondered whether IGF2BP2 might play an adaptive role during cardiac stress and recovery. Enhanced expression of an IGF2BP2 transgene in a conditional, inducible mouse line leads to dilated cardiomyopathy (DCM) and death within 3-4 weeks in newborn or adult hearts. Downregulation of the transgene after 2 weeks, however, rescues these mice, with complete recovery by 12 weeks. Hearts overexpressing IGF2BP2 downregulate sarcomeric and mitochondrial proteins and have fragmented mitochondria and elongated, thinner sarcomeres. IGF2BP2 is also upregulated in DCM or myocardial infarction patients. These results suggest that IGF2BP2 may be an attractive target for therapeutic intervention in cardiomyopathies.

VICKZ1 enhances tumor progression and metastasis in lung adenocarcinomas in mice.

The VICKZ (Igf2bp) family of RNA binding proteins regulate RNA function at many levels, including intracellular RNA localization, RNA stability, and translational control. One or more of the three VICKZ paralogs are upregulated in many different types of cancers. Here, we show how VICKZ1 enhances, and dominant negative VICKZ1 inhibits, cell migration, growth in soft agar, and wound healing in a mouse lung adenocarcinoma cell line containing a constitutively active, mutant Kras. Similarly, modulation of VICKZ1 activity promotes or inhibits metastases upon implantation of these cells into syngeneic mice. To test these effects in a genetic model system, we generated a mouse with an inducible VICKZ1 transgene and found that isolated overexpression of VICKZ1 in the lungs had no noticeable effect on morphology. Although directed overexpression of mutant Kras in the lungs led to the formation of small adenomas, concurrent overexpression of VICKZ1 remarkably accelerated tumor growth and formation of pulmonary adenocarcinomas. VICKZ1-containing ribonucleoprotein complexes are highly enriched in Kras mRNA in lung adenocarcinoma cells, and Kras signaling is enhanced in these cells by overexpression of VICKZ1. Analysis of lung carcinoma patients reveals that elevated VICKZ1 expression correlates with lower overall survival; this reduction is dramatically enhanced in those patients bearing a mutant Kras gene. Our study reveals that RNA binding proteins of the VICKZ family can synergize with Kras to influence signaling and oncogenic activity.