LARP4B

Official Full Name

La ribonucleoprotein 4B

Organism

Homo sapiens

GeneID

23185

Background

This gene encodes a member of an evolutionarily conserved protein family implicated in RNA metabolism and translation. Members of this family are characterized by the presence of an La motif, which is often located adjacent to one or more RNA recognition motifs (RRM). Together, the two motifs constitute the functional region of the protein and enable its interaction with the RNA substrate. This protein family is divided into five sub-families: the genuine La proteins and four La-related protein (LARP) sub-families. The protein encoded by this gene belongs to LARP sub-family 4. It is a cytoplasmic protein that may play a stimulatory role in translation. [provided by RefSeq, Oct 2012]

Synonyms

LARP5; KIAA0217;

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Detailed Information

Recent Progress

The gene Larp4b encodes a member of an evolutionarily conserved protein family implicated in RNA metabolism and translation. Members of this family are characterized by the presence of a La motif, which is often located adjacent to one or more RNA recognition motifs (RRM). Together, the two motifs constitute the functional region of the protein and enable its interaction with the RNA substrate. This protein family is divided into five sub-families: the genuine La proteins and four La-related protein (LARP) sub-families. The protein encoded by this gene belongs to LARP sub-family 4. It is a cytoplasmic protein that may play a stimulatory role in translation.

mRNAs are key molecules in gene expression and subject to diverse regulatory events. Regulation is accomplished by distinct sets of trans-acting factors that interact with mRNAs and form defined mRNA-protein complexes (mRNPs). The resulting mRNP code determines the fate of any given mRNA and thus controls gene expression at the post-transcriptional level. The LARP4B belongs to an evolutionarily conserved family of RNA-binding proteins characterized by the presence of a La-module implicated in direct RNA binding. Previous experiments have shown direct interactions of LARP4B with factors of the translation machinery. This finding, along with the observation of an association with actively translating ribosomes, suggested that LARP4B is a factor contributing to the mRNP code. To gain insight into the function of LARP4B in vivo, researchers tested its mRNA association at the transcriptome level and its impact on the proteome. Further analysis showed that LARP4B binds to a distinct set of cellular mRNAs by contacting their 3' UTRs. Moreover, reduction of cellular LARP4B levels led to a marked destabilization of its mRNA targets and consequently their reduced translation. These data identified LARP4B as a component of the mRNP code that influences the expression of its mRNA targets by affecting their stability.

Researchers also identified LARP4B as a candidate tumor-suppressor gene in glioma. LARP4B expression was consistently decreased in human glioma stem cells and cell lines compared with normal neural stem cells. Moreover, heterozygous deletion of LARP4B was detected in nearly 75% of glioblastomas in the Cancer Genome Atlas database. LARP4B loss was also associated with low expression and poor patient survival. Overexpression of LARP4B in glioma cell lines strongly inhibited proliferation by inducing mitotic arrest and apoptosis (Fig.1). The expression levels of CDKN1A and BAX were also upregulated upon LARP4B overexpression, and the growth-inhibitory effects were partially dependent on p53 (TP53) activity in cells expressing wild-type, but not mutant p53. Further analysis revealed that the La module, which is responsible for the RNA chaperone activity of LARP4B, was important for the growth-suppressive effect and was associated with BAX mRNA. Finally, LARP4B depletion in p53 and Nf1-deficient mouse primary astrocytes promoted cell proliferation and led to increased tumor size and invasiveness in xenograft and orthotopic models. These data provided strong evidence that LARP4B can serve as a tumor-suppressor gene in glioma, encouraging further exploration of the RNA targets potentially involved in LARP4B-mediatd growth inhibition.

Fig. 1. LARP4B overexpression induces mitotic arrest and apoptosis of glioma cell lines. (Koso et al, 2016)

References:

Küspert, M., Murakawa, Y., Schäffler, K., Vanselow, J. T., Wolf, E., & Juranek, S., et al. (2015). Larp4b is an au-rich sequence associated factor that promotes mrna accumulation and translation. Rna-a Publication of the Rna Society, 21(7), 1294-305.
Koso, H., Yi, H., Sheridan, P., Miyano, S., Ino, Y., & Todo, T., et al. (2016). Identification of rna-binding protein larp4b as a tumor suppressor in glioma. Cancer Research, 76(8), 2254-2264.
Blagden, S., Schneider, C., & Fischer, U. (2016). Loss of larp4b, an early event in the tumorigenesis of brain cancer?. Translational Cancer Research, 5(S6), S1196-S1199.
Zhang, Y., Peng, L., Hu, T., Wan, Y., Ren, Y., & Zhang, J., et al. (2015). La-related protein 4b maintains murine mll-af9, leukemia stem cell self-renewal by regulating cell cycle progression. Experimental Hematology, 43(4), 309-318.e2.
Mattijssen, S., & Maraia, R. J. (2015). Larp4 is regulated by tumor necrosis factor alpha in a tristetraprolin-dependent manner. Molecular & Cellular Biology, 36(4), 574-584.

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