Abstract
Tumour suppressor proteins, such as p53, BRCA1, and ABC, play key roles in preventing the development of a malignant phenotype, but those that function as transcriptional regulators need to enter the nucleus in order to function. The export of proteins between the nucleus and cytoplasm is complex. It occurs through nuclear pores and exported proteins need a nuclear export signal (NES) to bind to nuclear exportin proteins, including CRM1 (Chromosomal Region Maintenance protein 1), and the energy for this process is provided by the RanGTP/RanGDP gradient. Due to the loss of DNA repair and cell cycle checkpoints, drug resistance is a major problem in cancer treatment, and often an initially successful treatment will fail due to the development of resistance. An important mechanism underlying resistance is nuclear export, and a number of strategies that can prevent nuclear export may reverse resistance. Examples include inhibitors of CRM1, antibodies to the nuclear export signal, and alteration of nuclear pore structure. Each of these are considered in this review.
Highlights
IntroductionCancer is a disease characterised by genetic mutations leading to uncontrollable cell division and invasion into local tissue, which eventually spreads into distant tissue, a process known as metastasis
Cancer is a disease characterised by genetic mutations leading to uncontrollable cell division and invasion into local tissue, which eventually spreads into distant tissue, a process known as metastasis.Cancer is a very heterogeneous disease, it has been proposed and widely accepted that there are hallmark features common to most cancer cells (Figure 1) [1], the development of which is driven by mutations
DNA repair and cell cycle checkpoints, drug resistance is a major problem in cancer treatment, and often an initially successful treatment will fail due to the development of resistance
Summary
Cancer is a disease characterised by genetic mutations leading to uncontrollable cell division and invasion into local tissue, which eventually spreads into distant tissue, a process known as metastasis. A key component of this response is the p53 tumour suppressor gene that controls cell cycle arrest, and which can if catastrophic damage occurs, induce apoptosis (i.e., programmed cell death) [2] These mechanisms prevent mutations from being passed onto future generations of cells. The acquisition of mutations may be viewed as a stepwise process and often there is a failure of DNA repair mechanisms When these mechanisms are disrupted, the cancer cells can acquire mutations at a rapid rate and acquire hallmark features. A nuclear pores in a selective, active process facilitated number mobile transport total molecular mass of 125 mDa and contains up to 100 proteins known as nucleoporins (Nups). The entry and exit of macromolecules from the nucleus is regulated by this complex
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