The RNA-binding protein La contributes to cell proliferation and CCND1 expression

Abstract

The La protein is an essential RNA-binding protein implicated in different aspects of RNA metabolism. Herein, we report that small interfering (siRNA)-mediated La depletion reduces cell proliferation of different cell lines concomitant with a reduction in cyclin D1 (CCND1) protein. To exclude off-target effects we demonstrate that exogenous La expression in La-depleted cells restores cell proliferation and CCND1 protein levels. In contrast, proliferation of immortalized CCND1 knockout cells is not affected by La depletion, supporting a functional coherence between La, CCND1 and proliferation. Furthermore, we document by reversible in vivo crosslinking and ribonucleoprotein (RNP) immunoprecipitation an association of the La protein with CCND1 messengerRNA and that CCND1 internal ribosome entry site (IRES)-dependent translation is modulated by La protein level within the cell. In addition, we show elevated La protein expression in cervical cancer tissue and its correlation with aberrant CCND1 protein levels in cervical tumor tissue lysates. In conclusion, this study establishes a role of La in cell proliferation and CCND1 expression and demonstrates for the first time an overexpression of the RNA-binding protein La in solid tumors.

Postchemotherapy and Tumor-Selective Targeting with the La-Specific DAB4 Monoclonal Antibody Relates to Apoptotic Cell Clearance

“…The La antigen is a novel target for the detection of dead tumor cells because it is overexpressed in a variety of cultured human malignant cells (16,28) and in human malignant tissues (28)(29)(30). As La becomes accessible after cytotoxic treatment of tumor cells (16,20), examining the prevalence of La provides a new target for exploring tumor responses to treatment.…”

The RNA chaperon activity of the human La protein (LARP3)

“…It has been shown recently that La protein depletion causes a massive drop in cyclin D1 protein levels and stimulates cyclin D1 IRES-mediated translation [17] . Mapping the La binding site in cyclin D1 mRNA revealed that La binds in close proximity to the translation start site [36] .…”

“…tRNAs, mircoRNAs, snoRNAs [6][7][8] [ [9][10][11] and binds to long viral and cellular mRNAs. Besides its LAM:RRM1-mediated interaction with the oligo(U) 3'-termini common to nascent RNA polymerase III transcripts such as pre-tRNAs [12] , human La can bind to the 5'-terminus of mRNAs referred to as terminal polypyrimidine tract (TOP) mRNAs [13][14][15] , and internal RNA elements in RNAs such as MDM2 [16] , cyclin D1 [17] , XIAP [18] , human immunodeficiency virus [19] , hepatitis C [20] and A virus [21] and polio virus [22] .…”

“…First it has been shown that La expression is elevated in different cancer cell lines as well as in chronic myelogenous leukemia, and more recently it has been revealed that La is overexpressed in various types of solid tumor tissue when compared to normal adjacent tissue [16,17,23,24] . This finding sparked the interesting question whether the La protein promotes tumor pathogenesis when overexpressed.…”

“…This finding sparked the interesting question whether the La protein promotes tumor pathogenesis when overexpressed. Recent studies have shown that the human La protein supports proliferation, migration, and invasion of cancer cells [17,23] . The murine La protein has a small amino acid insertion in the C-terminal domain and is 7 amino acids longer than the human La.…”