Molecular dissection of nucleolin's role in growth and cell proliferation: new insights

Abstract

Cells require optimum protein synthetic activity in order to support cell proliferation, maintain homeostatic and metabolic integrity, and repair damage. Since growth depends on protein synthesis through ribosome biogenesis, the control of biosynthesis of ribosomes is necessarily a key element for control of growth. Nucleolin is a major nucleolar protein of exponentially growing eukaryotic cells, which is directly involved in the regulation of ribosome biogenesis and maturation. The highly conserved nucleolin contains three major domains through which it controls the organization of nucleolar chromatin, packaging of pre-RNA, rDNA transcription, and ribosome assembly. Numerous reports have implicated the involvement of nucleolin either directly or indirectly in the regulation of cell proliferation and growth, cytokinesis, replication, embryogenesis, and nucleogenesis. Nucleolin, an RNA binding protein, is also an autoantigen, a transcriptional repressor, and a switch region targeting factor. In addition, nucleolin exhibits autodegradation, DNA and RNA helicase activities, and DNA-dependent ATPase activity. An interesting aspect of nucleolin action is that it is a target for regulation by proteolysis, methylation, ADP-ribosylation, and phosphorylation by CKII, cdc2, PKC-xi, cyclic AMP-dependent protein kinase, and ecto-protein kinase. For these and other reasons, nucleolin is fundamental to the survival and proliferation of cells. Considerable progress has been made in recent years with the identification of new nucleolin binding proteins that may mediate these many nucleolin-dependent functions. Nucleolin also functions as a cell surface receptor, where it acts as a shuttling protein between cytoplasm and nucleus, and thus can even provide a mechanism for extracellular regulation of nuclear events. Exploration of the regulation of this multifaceted protein in a remarkable number of diverse functions is challenging.

ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity

“…Affinity chromatography using ADAMTS-2 as a bait and co-localization studies identified nucleolin as a potential membrane receptor for ADAMTS-2. Nucleolin was initially described as a nucleolar protein participating in the transcriptional control of ribosomal RNA genes, in ribosomes maturation and assembly, and in the nucleocytoplasmic transport of ribosomal components [40,41]. It has also been shown that nucleolin can translocate to the plasma membrane in some specific cell types such as endothelial cells and many transformed cells [42].…”

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

“…Nucleolin may be involved in cleavage of rRNA, acts as a chaperone in correct folding of pre-rRNA processing, and in repression of transcription (Allain et al 2000;Hiscox, 2002;Yang et al 1994). The amount of nucleolin is stable in proliferative cells, but it undergoes selfcleavage in quiescent cells (Chen et al 1991;Hiscox, 2002) and is also involved in process of cell growth and proliferation (Hiscox, 2002;Srivastava and Pollard, 1999). …”

PIKE mediates EGFR proliferative signaling in squamous cell carcinoma cells

“…38 Activated nucleolin is involved in various aspects of DNA and RNA metabolism 39 essential for cell proliferation. 40,41,47,48 We here demonstrate that in SCC cells EGF-induces activation of PI3K and PKC-z as well as nucleolin phosphorylation in the nucleus, and these processes require PLC-g1 and PIKE.…”

“…38 The activated nucleolin in the nucleus is fundamental to the survival and proliferation of cells. 40,41 To determine whether knockdown of PLC-g1 or PIKE altered EGF-induced nucleolin phosphorylation in human SCC cells, SCC4 cells were treated with siRNA for PLC-g1 or PIKE for 3 days and then with vehicle, EGF or fetal bovine serum for 7 min. Cells were harvested and nuclear lysates were isolated.…”