The pathways that lead to cancer are complex and poorly understood. How different proteins and the genes that encode for them play a role in the promotion or inhibition of tumor-inducing factors has been the subject of intense research over the years which has led to several intriguing and promising drug development targets. This article will discuss MBNL1 and its role in cancer development.
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The MBNL1 Protein
The MBNL1 protein is comprised of 370 amino acids. The protein binds to double-stranded CUG expansions of mRNA and has a role in the modulation of pre-mRNA splicing. There are several isoform variants of this protein (as well as two paralogs, MBNL2 and MBNL3) which are alternatively spliced. It has four Zinc Finger protein domains of C3H types.
It plays a dual function, both repressing and activating terminal muscle differentiation. As well as this dual function, MBNL1 also autoregulates alternative splicing of its pre-mRNA transcript. This autoregulation is also carried out by MBNL2 and MBNL3. The Zinc Finger domains play roles in both protein: protein and protein: RNA contacts (when bound to an oligonucleotide.
It is encoded for the MBNL1 gene. The MBNL1 protein has been shown to play a major role in Myotonic dystrophy, an abnormal muscular condition. It was originally described in Drosophila melanogaster, where the founding member of the human MBNL1 family was discovered. In mouse models, the lack of the MBNL1 gene led to observed cataracts and abnormalities in muscle development.
So far, even though several alternatively spliced variants have been discovered, only a few have been determined completely by studies into the protein. The variants are believed to have different binding and splicing specificities that are poorly understood.
Cancer and the Need for Novel Drug Development Targets
As has been previously mentioned, cancer researchers are constantly looking for novel drug development targets to provide new, more effective therapeutics and improve recovery and survival rates for the many millions of people worldwide who are diagnosed each year. Several potential targets have been identified by studies over the past few decades with varying degrees of success.
Conventional forms of treatment can sometimes even be detrimental to the patient. Therefore, the search for developing therapeutics which can specifically target tumors and the pathways which lead to tumorigenesis whilst negating the harmful side-effects of traditional cancer therapies are of key concern to researchers working in the field.
MBNL1 is a protein that is especially attractive to scientists looking to develop novel therapies and drugs due to its RNA splicing activities and for this reason, has been the target of several studies over the past few years.
The MBNL1 Protein and Cancer
Cancer is a genetic disease. Abnormalities, either hereditary or acquired during the lifetime due to factors such as smoking, diet, and radiation exposure, lead to the development of cancer. There are several ways that cancer can develop from a perturbation in the transcription of proteins and the expression of genes and mRNA. It affects millions of patients worldwide and remains one of the main pathologies in humans.
It, therefore, makes sense that the ability to interrupt the genetic triggers that lead to abnormal cellular functions and, thus, tumor formation, is incredibly attractive to researchers. The extent of alternative splicing in cancer and the role the process plays are well-documented. Research into the MBNL1 protein, how its isoforms affect cancer development in opposing and various ways, and its potential as a drug development target are ongoing.
Some studies into MBNL1’s potential for treating different types of cancer are listed below.
Suppression of Breast Cancer Metastatic Colonization by MBNL1
One of the defining features of metastatic cancer is post-transcriptional deregulation. Many microRNAs have been shown to play roles within metastatic progression but the specific mechanisms of RNA-binding proteins are still largely unknown.
The MBNL1 gene is a robust and effective suppressor of multiorgan breast cancer metastasis due to its ability to bind the 3’ untranslated regions of both DBNL and TACC1, which are metastasis suppressors. By binding to these two genes, MBNL1 enhances the stability of their transcripts, suppressing cell invasiveness, and reducing the likelihood of metastatic relapse at elevated levels.
There seems to be an RNA-binding protein-mediated post-transcriptional network that plays an intimate role in regulating breast cancer metastasis. Research into how MBNL1 can play a part in this pathway is positive.
MBNL1 Overexpression Contributes to Tumor Propagation in Infant Leukemia
Infant leukemia unfortunately still has a poor prognosis in a significant number of cases and is caused by reciprocal translocations of the MLL-gene. MBNL1 overexpression is common in both acute myeloid and acute lymphoid leukemia. A study published by Itskovitch et al. showed that by inhibiting this overexpression using shRNA knockdown experiments, propagation of MLLr leukemic cells was vastly reduced.
The study showed extremely promising results, including a 71% reduced growth of MLLr cells compared to the control group, demonstrating the detrimental role overexpression of the MBNL1 gene plays in this type of cancer.
In Conclusion
The MBNL1 protein and the gene which encodes for it plays a complex role in the cellular functions of humans, and differences in expression can lead to a variety of interesting outcomes. Due to the intimate role it plays and how this relates to cancer development research into MBNL1 is ongoing.
Therapeutics which promote or suppress MBNL1 expression are looking like they may provide novel ways to treat cancer shortly.