Roles of heterogeneous nuclear ribonucleoproteins A and B in cell proliferation

Abstract

IntroductionHeterogeneous nuclear ribonucleoprotein particle proteins (hnRNPs) are abundant, multi-tasking proteins that play a central role in RNA metabolism. They are involved in packaging nascent hnRNA, alternative RNA splicing, mRNA export from the nucleus, and cytoplasmic trafficking, stability and translation (Dreyfuss et al., 2002;Krecic and Swanson, 1999;Shyu and Wilkinson, 2000;Weighardt et al., 1996). They also have an as yet poorly defined role in telomere maintenance.More than 20 hnRNPs, many of which are characterised by possession of RNA-recognition motifs (RRMs), have been identified. The hnRNPs A/B are the major components of the 40S particles that package hnRNA. This packaging was originally envisaged to mimic that of histones in nucleosomes but this analogy appears to be inappropriate as the levels of the core proteins are not stoichiometric: they differ markedly between cell types, and their association with RNA is dependent on the nucleic acid sequence (Dreyfuss et al., 1993). However, given the role of these core particles in hnRNA packaging one might anticipate a correlation between the abundance of their proteins and the transcriptional activity in the cell. This is borne out experimentally: there is a marked difference in the concentration of hnRNP A1 between resting or slowly dividing cells and rapidly dividing cells. In the latter, hnRNPs A1 and A2 have been proposed to be present at similar levels. But hnRNP A1, which is abundant in a range of human, hamster and mouse proliferating cells, is present at markedly lower levels in confluent or resting cells, whereas hnRNP A2 is less affected (Celis et al., 1986;LeStourgeon, 1978).The levels of hnRNPs A/B differ not only between proliferating and resting cells: some also fluctuate during the cell cycle (Leser and Martin, 1987;Minoo et al., 1989). In HeLa cells hnRNPs A2 and B1 are synthesized in the G1 phase, and their levels fall in G2 and M phases, with hnRNP B1 protein level falling more markedly . The relative and absolute levels of these two proteins also differ markedly between tissues, both being particularly abundant in rat brain, testis, lung, spleen and ovary (Kamma et al., 1999;Ma et al., 2002).Many genes show a correlation between strong expression in proliferating cancer cells and the fluctuations in the protein level across the cell cycle (Dreyfuss et al., 1993;Whitfield et al., 2002). The levels of hnRNP A/B proteins are of particular interest as it has been suggested that upregulation of some members of this protein family is associated, as either a cause or consequence, with cellular proliferation and cancer. The hnRNP A2 and its longer B1 isoform are expressed at an early stage in a variety of tumours and have been proposed as early markers for cancer, especially lung cancer (Fielding et al., 1999;Mulshine et al., 2002;Pino et al., 2003;Sueoka et al., 1999;Whitfield et al., 2002;Zhou et al., 1996) and possibly breast cancer (Zhou et al., 2001a). The upregulation of hnRNP A2/B1 in cancer parallels its expression in lung dev...

Functional Impact of Heterogeneous Nuclear Ribonucleoprotein A2/B1 in Smooth Muscle Differentiation from Stem Cells and Embryonic Arteriogenesis

“…hnRNPA2/B1 has been reported as a gene transcriptional activator or repressor in different gene regulations. For example, hnRNPA2 transcriptionally represses expression of vitamin D receptor, but it works more like an activator for Brca1 gene transcription (14,38). In this study, our current findings also revealed that hnRNPA2/B1 is an activator that regulates SMC Sm␣a and Sm22 gene expression during SMC differentiation from ES cells.…”

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

“…For one, it was found to have a protective effect against apoptosis, possibly in part through an effect on AS of caspase-2 pre-mRNA (Jiang et al 1998). In addition, depletion of hnRNP A/B proteins in Colo16 cells resulted in reduced proliferation, with hnRNP A2 playing a particularly important role (Jiang et al 1998;He et al 2005). Consistent with an important role in tumors, siRNA-mediated knockdown of hnRNP A1/A2 in cancer cells, but not normal cells, can result in apoptosis (Patry et al 2003).…”

Role of multi-hnRNP nuclear complex in regulation of tumor suppressor ANXA7 in prostate cancer cells

“…Suppression of hnRNPA2 increases p21 (He et al, 2005), while downregulation of hnRNPK and p21 switches between apoptosis and growth arrest induced by p53 (Enge et al, 2009). Hence, the multi-hnRNP-regulated ANXA7 could interfere with p53 cell survival pathways in p53/PTEN-null PC3.…”