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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Role of tumor suppressor p53 and micro-RNA interplay in multiple myeloma pathogenesis
Jahangir Abdi1,2, Nasrin Rastgoo1,2, Lihong Li3
1Division of Molecular and Cellular Biology, Toronto General Research Institute, Toronto, Canada.
Abstract:
The molecular mechanisms underlying dysregulated wild type (wt) p53 in multiple myeloma (MM) have been subjects of intense investigation for years. Indeed, correlation of rarely occurring TP53 gene mutations or deletions with adverse clinical outcomes in MM patients is strongly established, while in majority of cases wtp53 seems to be non-functional or dysregulated bearing a high clinical impact. Interestingly, findings from recent investigations show that micro-RNAs (miRNAs) may contribute to suppression of wtp53 in MM, as they are now known to function as key regulatory elements in the p53 network. This area is shedding new light on understanding the biologic effects of dysregulated p53 in MM pathogenesis especially drug resistance. miRNAs such as miR-125b (oncomiR) or miR-34a (tumor suppressor-miR) can be negative or positive regulators of wtp53 function, respectively, with specific effects on MM cell viability. On the other hand, our knowledge of miRNA interaction with mutant (mt) p53 in MM, which is rather related to disease progression and resistance to therapy, is limited which demands in-depth exploration. Here, we will put forward the current knowledge on miRNA-p53 interaction in MM and its role in MM pathogenesis including drug resistance. We will also highlight the pre-clinical approaches for therapeutic application of miRNAs targeting p53 pathway.
Insights
MicroRNAs (miRNAs) regulate wild-type p53 function in multiple myeloma (MM), impacting drug resistance. Further research into miRNA interactions with mutant p53 is crucial for understanding MM progression and developing new therapies.
Area of Science:
- Molecular Biology
- Oncology
- Gene Regulation
Background:
- Wild-type p53 (wt p53) is frequently dysregulated in multiple myeloma (MM), correlating with poor clinical outcomes.
- While TP53 mutations are rare, wt p53 often appears non-functional in MM, significantly impacting disease progression.
- Micro-RNAs (miRNAs) are emerging as key regulators of the p53 network and may contribute to wt p53 suppression in MM.
Purpose of the Study:
- To review current knowledge on miRNA-p53 interactions in MM pathogenesis.
- To elucidate the role of these interactions in MM drug resistance.
- To highlight preclinical therapeutic strategies targeting the miRNA-p53 axis in MM.
Main Methods:
- Literature review of studies investigating miRNA and p53 interactions in multiple myeloma.
- Analysis of miRNA regulatory roles (e.g., miR-125b, miR-34a) on wt p53 function and MM cell viability.
- Exploration of current understanding of mutant p53 (mt p53) interactions with miRNAs in MM.
Main Results:
- Specific miRNAs like miR-125b (oncomiR) and miR-34a (tumor suppressor-miR) differentially regulate wt p53, affecting MM cell viability.
- Dysregulated p53, influenced by miRNAs, plays a significant role in MM pathogenesis and drug resistance.
- Knowledge regarding miRNA interactions with mt p53 in MM is limited but linked to disease progression and therapy resistance.
Conclusions:
- miRNAs are critical modulators of p53 function in multiple myeloma, influencing both normal and mutant forms.
- Understanding these miRNA-p53 interactions is vital for deciphering MM pathogenesis and overcoming drug resistance.
- Targeting the miRNA-p53 pathway presents promising preclinical therapeutic avenues for MM treatment.
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