Abstract
Myeloid cell leukemia 1 (MCL1) is a key anti-apoptotic protein belonging to the BCL-2 protein family. To preserve normal cellular homeostasis, cells must maintain strict control over MCL1 expression. Overexpression of MCL1 has been identified as a key contributor to tumorigenesis, and further enables resistance to a number of anti-cancer chemotherapies. Thus, there is an ongoing interest to develop selective MCL1 inhibitors. In order to better target MCL1, it is essential to understand the molecular mechanisms that regulate MCL1 expression in cells. While MCL1 expression is tightly controlled by multiple mechanisms, the post-transcriptional regulation of MCL1 mRNA is poorly studied. Our previous work identified that polypyrimidine tract binding protein 1 (PTBP1) binds to MCL1 mRNA and represses MCL1 expression by destabilizing MCL1 mRNA. In this report, we show that PTBP1 modulates MCL1 expression by regulating the microRNA (miRNA) direction of the miRNA-induced silencing complex (miRISC) to MCL1. We demonstrate that PTBP1 enhances miR-101-guided AGO2 interaction with MCL1, thereby regulating miR-101-induced apoptosis and clonogenic cell survival inhibition in cells. Taken together, not only do these studies expand our understanding on the regulation of MCL1, they also demonstrate that PTBP1 and miRNAs can function cooperatively on a shared target mRNA.
Highlights
Myeloid cell leukemia 1 (MCL1), an anti-apoptotic member of the BCL-2 protein family, is a key regulator of survival that inhibits intrinsic apoptosis or programmed cell death[1]
The effects of polypyrimidine tract binding protein 1 (PTBP1) on MCL1-targeting miRNA expression Based on our previous analysis of PTBP1 Crosslinkingimmunoprecipitation Sequencing (CLIP-seq), which identified multiple binding sites in the 3′ untranslated region (3′-UTR) of MCL18, we hypothesized that PTBP1 regulates MCL1 expression via the miRNAs/miRNA-induced silencing complex (miRISC) complex
Studying the basic mechanisms of posttranscriptional control is necessary to gain a comprehensive understanding of how gene expression is regulated at different levels and how aberrant posttranscriptional regulation is involved in multiple diseases, including cancer
Summary
Myeloid cell leukemia 1 (MCL1), an anti-apoptotic member of the BCL-2 protein family, is a key regulator of survival that inhibits intrinsic apoptosis or programmed cell death[1]. MCL1 functions as an anti-apoptotic regulator in two roles. MCL1 directly interacts with the activator BH3-only proteins such as BID, BIM, and PUMA thereby blocking their ability to initiate BAK and BAX oligomerization[1,2]. Because of these roles, strict regulation of MCL1 expression is essential for normal cellular homeostasis. MCL1 expression is tightly controlled by multiple transcriptional, post-transcriptional, Official journal of the Cell Death Differentiation Association
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