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Published on: July 15, 2018
The CRM1 nuclear export protein in normal development and disease
Kevin T Nguyen1, Michael P Holloway, Rachel A Altura
1Department of Pediatrics, Division of Pediatric Hematology-Oncology, Hasbro Children's Hospital and The Warren Alpert Medical School at Brown University Providence, Rhode Island, USA.
Summary
Chromosomal Maintenance 1 (CRM1) facilitates nuclear export of proteins and RNA. Inhibiting CRM1 shows promise as a cancer therapy by inducing cancer cell death.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- CRM1 (Exportin 1) is the primary mammalian export protein, crucial for transporting macromolecules across the nuclear membrane.
- CRM1 is involved in nuclear-cytosolic transport, centrosome duplication, and spindle assembly, particularly after DNA damage.
Purpose of the Study:
- To explore the therapeutic potential of inhibiting CRM1 in cancer treatment.
- To understand CRM1's role in regulating tumor suppressors and oncoproteins.
Main Methods:
- Analysis of CRM1's crystal structure and its interaction with RanGTP and cargo proteins via Nuclear Export Signals (NES).
- Observation of CRM1's role in binding various tumor suppressors and oncoproteins (e.g., p53, BRCA1, Survivin).
Main Results:
- Imbalances in cytosolic levels of CRM1 cargo proteins are linked to cancer progression.
- Inhibition of CRM1 using small molecules leads to cancer cell death by disrupting cargo binding.
Conclusions:
- CRM1 inhibition represents a viable therapeutic strategy for cancer.
- Further research is needed to determine if specific CRM1 cargo proteins are essential for the observed anti-cancer effects.
Related Concept Videos
01:42Nuclear Export
The nucleus restricts several proteins within and allows others to pass. The restricted proteins possess a nuclear retention sequence or NRS, anchoring them to the nuclear lamins and preventing their transport to the cytosol. The non-restricted proteins, after their synthesis, are transported to their site of action, such as the cytosol or other organelles, with the help of nuclear export signals or NES.
NES are of three types- the canonical 10-residue long leucine-rich signal and other...
NES are of three types- the canonical 10-residue long leucine-rich signal and other...
02:31Nuclear Export of mRNA
Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
02:31Nuclear Export of mRNA
Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
01:42Directionality of Nuclear Transport
Ras-related nuclear protein or Ran is a small G protein that cycles between its GTP and GDP bound states. Ran specific regulators, a Ran GTPase Activating Protein or RanGAP present in the cytosol and a Ran guanine nucleotide exchange factor or RanGEF present inside the nucleus regulate GTP/GDP exchange. A high concentration of GTP inside the cells, in addition to this asymmetric distribution of Ran-specific regulators, leads to a higher RanGTP concentration inside the nucleus. This...
01:45Regulation of Nuclear Protein Sorting
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
01:34Nuclear Protein Sorting
Nuclear protein sorting is the selective trafficking of histones, polymerases, gene regulatory proteins into the nucleus and exporting RNAs and ribosomes to the cytosol. It is a tightly controlled process that regulates gene expression within a cell.
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...