The nucleolar protein nucleolin conducts multiple activities because it contains multiple phosphorylation sites. The nucleolar phosphoprotein nucleolin mainly stays in the nucleolus while moving between the nucleus and cytoplasm. The multifunctional nucleolin protein operates as an essential component within the nucleolus inside the nucleus. The nucleolar protein nucleolin functions as a multifunctional molecule that directs key biological processes including cell growth and proliferation together with apoptosis and nucleic acid metabolism.
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Structure of Nucleolin
- N-terminal oligomerization domain: The protein self-assembles into a pentamer through its N-terminal oligomerization domain.
- C-terminal nucleic acid-binding domain: mediates binding to rRNA and DNA.
- C-terminal nuclear export signal (NES): responsible for the nuclear-cytoplasmic transport of nucleolin.
Fig 1. Structure of NCL (Tonello, F., et al. 2022).
Main Functions of Nucleolin
Nucleolin compounds contain nucleobases and pentoses which make up the essential structure of cellular nucleic acids. RNA and DNA structures rely on nucleolin as their fundamental component. Cells use nucleolin to form nucleotides through phosphate binding before it engages in nucleic acid synthesis. Certain nucleolins including adenosine function as essential components in cellular energy metabolism with a primary focus on ATP (adenosine triphosphate) synthesis and metabolic processes.
Ribosome Biosynthesis
As a nucleolar scaffold protein nucleolin plays a role in ribosomal subunit assembly and rRNA processing. Maintain correct folding of ribosomal proteins alongside ribosomal subunit assembly.
Cell Cycle Regulation
Nucleolin controls the cell cycle by modifying tumor suppressor proteins p53 and ARF (p14ARF/p19ARF). Nucleolin functions as a phosphorylation modulator which helps to induce cell cycle arrest and DNA repair mechanisms during DNA damage responses.
DNA Repair and Stability Maintenance
DNA replication and repair processes prevent chromosome aberrations through active participation. The molecule orchestrates chromatin structure by interacting with nucleosomes and histone deacetylases (HDACs).
Apoptosis
Under oxidative stress or DNA damage conditions nucleolin relocates to the cytoplasm to regulate apoptosis-controlling proteins including BAX. Mitochondrial pathways experience effects from this process which leads to the stimulation or prevention of apoptosis.
Nucleolus-cytoplasm Transport
Nucleolin's nuclear export signal (NES) facilitates its movement through the nucleolus and nucleus until it reaches the cytoplasm where it regulates protein positioning and activity.
Role of Nucleolin in Cancer
Studies show that nucleolin regulates genes linked to the cell cycle that results in enhanced tumor cell growth. Through apoptosis pathway modulation nucleolin regulates anti-apoptotic protein expression which enhances cancer cell survival. Cancer treatments lose their effectiveness due to the development of resistance mechanisms within cancer cells. Nucleolin primarily exists within the nucleolus but also appears in the cytoplasm and cell membrane. Protein placement within cellular structures plays a vital role in the progression of cancer.
Nucleolar Localization
Cancer cells demonstrate increased nucleolin expression which leads to enhanced ribosome production and improved protein translation capabilities which supports cancer cell growth.
Cytoplasmic Localization
The protein executes functions in mRNA transport and translation control while driving oncogene expression including c-Myc.
Cell Membrane Localization
The receptor located on the cell surface communicates with growth factors like VEGF which results in the stimulation of both angiogenesis and tumor invasion. Nucleolin presence on cell membranes serves both as a biomarker for cancer detection and as a point for therapeutic intervention.
Exocytosis
Nucleolin functions as an intercellular communication molecule within the cancer cell microenvironment to advance tumor progression.
Nucleolin and Disease
Acute Myeloid Leukemia (AML)
Acute myeloid leukemia (AML) presents nucleolin gene mutation as one of its most prevalent genetic alterations which occurs in approximately 30% of cases. The nucleolin c+ mutation generates an enhanced nuclear export signal which disrupts nucleolin transport to the cytoplasm thereby disturbing normal hematopoietic function.
Tumors
Nucleolin functions as an oncogene that triggers cell proliferation and tumor advancement in various solid tumors including breast cancer, lung cancer, and gastric cancer.
Neurodegenerative Diseases
Neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) could involve nucleolin which when abnormally aggregated impacts neuronal survival.
Nucleolin Participates in Important Physiological Activities
The cell nucleus includes nucleolin as a multifunctional protein that guides ribosome production and oversees functions such as cell division control, DNA repair processes as well as programmed cell death. Gene mutations of nucleolin play a significant role in acute myeloid leukemia (AML) and other cancer types which makes nucleolin an important biological target for tumor treatment. Future studies about nucleolin will concentrate on developing targeted therapies and basic scientific research.
Nucleolin acts as an essential regulator of ribosome biogenesis and also directs mRNA metabolism together with chromatin remodeling and signal transduction processes. The altered subcellular localization of nucleolin creates conditions for increased tumor growth and invasion alongsid. Nucleolin binds to pre-rRNA to regulate RNA polymerase I activity while promoting shearing during the first step of rRNA processing that leads to proper ribosome formation.
References
- Mongelard, F., et al. Nucleolin: a multiFACeTed protein. Trends in cell biology. 2007, 17(2): 80-86.
- Abdelmohsen, K., et al. RNA-binding protein nucleolin in disease. RNA biology. 2012, 9(6): 799-808.
- Tonello, F., et al. Nucleolin: a cell portal for viruses, bacteria, and toxins. Cellular and Molecular Life Sciences. 2022, 79(5): 271.
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