Our Science – Lal Website
Ashish Lal, Ph.D.
A majority (>70%) of the eukaryotic genome is transcribed, of which only 2% represents protein-coding sequences. Among the several types of non-coding RNAs, microRNAs (miRNAs) and long non-coding (lncRNAs) have gained significant attention due to their roles in vital cellular functions, including proliferation and survival. MiRNAs directly inhibit mRNA stability and/or translation. LncRNAs activate or repress gene expression via a variety of mechanisms including transcription and splicing. Deregulation of miRNAs and lncRNAs has been correlated with human diseases, including cancer. Recently, we and others have identified select miRNAs and lncRNAs transactivated by p53, the most frequently mutated gene in human cancer. A deeper understanding of the biology of these miRNAs and lncRNAs is critical in determining their potential in cancer therapy. The goal of my laboratory is to investigate the function of miRNAs and lncRNAs in p53 signaling, an intriguing question in cancer biology and therapeutics.
Mammalian miRNAs bind to target mRNAs via partial complementarity. A single miRNA can regulate the expression of hundreds of mRNAs and due to partial miRNA-mRNA base-pairing, identifying miRNA targets is challenging (Thomas et al., Nat Struct Mol Biol, 2010). Recently, we have developed a biochemical approach to identify endogenous mRNAs bound to a transfected biotinylated-miRNA (Lal et al., PLoS Genet, 2011). Combining this strategy with bioinformatics identified a network of genes and canonical pathways regulated by the p53-regulated miRNA miR-34a and the tumor suppressor miR-24 (Lal et al., Mol Cell 2009; Lal et al., Nat Struct Mol Biol 2009). Our ongoing and future research is focused on investigating the regulation and function of miRNAs in p53 signaling. In a recent publication (Li et al., Mol Cell Biol, 2013) we have identified a novel function of the p53-target p21, in regulation of miRNAs. We have shown that p21 inhibits the epithelial-mesenchymal transition (EMT) by regulating the expression of the miR-183-96-182 cluster.
Our ongoing studies have also identified novel miRNAs and lncRNAs that are transactivated by p53 during the DNA damage response. We believe that a subset of these p53-regulated non-coding RNAs may not only regulate a proportion of the p53 transcriptome to exert tumor suppressor effects but these non-coding RNAs may also be utilized for future cancer therapeutics. To examine the function of lncRNAs, we are generating knockouts and also developing a novel method to identify the RNA-binding proteins and regions of the genome bound by the lncRNAs in vivo.
Parallel to the above-mentioned studies focused on non-coding RNAs downstream of wild-type p53, we are also interested in their role in mutant p53 gain-of-function. Disruption of p53 function, through missense mutations in TP53, is a common feature in a majority of human cancers. However, there is now strong evidence that some mutant p53 proteins including p53R175H, p53R273H and p53R280K acquire novel gain-of-function activities that are entirely independent of wild-type p53, to enhance invasion, survival and metastasis. Although mutant p53 proteins typically lack DNA-binding activity, it is well-established that mutant p53 can regulate the transcription of hundreds of genes by inhibiting key transcription factors including the p53 family members, p63 and p73. Because miRNAs have been shown to regulate a majority of the biological processes modulated by mutant p53, we have recently investigated their role in mutant p53 gain-of-function. Our ongoing studies suggest that mutant p53 inhibits p63 to down-regulate the tumor suppressor miRNA let-7, resulting in increased invasion and metastasis in breast cancer. This study together with recent reports on mutant p53-regulated miRNAs suggests an important function of miRNAs in mediating the oncogenic effects of mutant p53.
We are utilizing cell and molecular biological approaches to investigate the function of specific miRNAs and lncRNAs downstream of p53 and also conducting studies in patient samples and in mice to examine their role in cancer pathogenesis. We anticipate that these studies will identify novel targets and pathways regulated by miRNAs and lncRNAs downstream of p53.
This page was last updated on 12/5/2013.