Human Molecular Genetics & Cancer Biology
The major research interests of our laboratory include 1) cellular and molecular basis of oral, liver and lung cancers with an aim to find therapeutic targets, and 2) next-generation sequencing based discovery of causative genes for following genetic disorders: primary microcephaly, microspherophakia, anencephaly, tuberous sclerosis complex, and Wilson disease. Currently, we are focusing on the following projects.
Identification of TSC2-regulated protein coding and non-coding RNA genes: Mutations in tumor suppressor TSC1 and TSC2 genes cause an autosomal dominant disorder, tuberous sclerosis complex (TSC). TSC1 and TSC2 proteins interact to form a complex, which negatively regulates mTORC1 in the PI3K-AKT-mTOR pathway, and in turn regulates cell proliferation. This is a well-known cytoplasmic function of these TSC genes. We and others have shown earlier that TSC1/hamartin localizes to the cytoplasm, whereas TSC2/tuberin shows nuclear as well as cytoplasmic localization. To elucidate the nuclear function of TSC2, we have used gene expression profiling of TSC2-overexpressing cells, luciferase reporter assay, siRNA knockdown, ChIP and EMSA techniques, and have shown for the first time that TSC2 also functions as a transcription factor and transcriptionally regulates Epiregulin, a ligand for EGFR. However, Epiregulin cannot be the only TSC2-regulated gene. Then, what are the other genes regulated by TSC2. The interested student(s) will thus explore and identify other (protein coding, microRNA and long non-coding RNA) genes, which are transcriptionally regulated by TSC2, using a variety of molecular and cell biology approaches such as microRNA microarray analysis and RNA Seq.
Identification of epigenetically-silenced microRNAs in oral cancer: In India, oral cancer is the leading cancer in males and the sixth most common malignancy in females. However, in spite of many advances in its treatment, the 5-year survival rate for oral cancer has remained unchanged during the last few decades. It is thus imperative to identify novel therapeutic targets for oral cancer. Studies have shown deregulation of microRNA expression and the contribution of microRNAs to the multi-step process of tumorigenesis, either as oncogenes or tumor suppressor genes. In recent years, microRNAs are being used as therapeutic targets in cancers. Given this background, the interested student(s) will identify and investigate the role and function of epigenetically-silenced (tumor suppressor) miRNAs in oral cancer, with an aim to exploit them as therapeutic targets, using a variety of molecular cell biology techniques, including oral tumor samples from patients and preclinical xenograft nude mice model.
Molecular consequences of mutations in ATP7B, coding for a copper transporter: Wilson disease (WD) is an autosomal recessive disorder, characterized by excessive deposition of copper in various parts of the body, mainly in the liver and brain. It is caused by mutations in ATP7B, which codes for a trans-Golgi network residing copper transporter. We have recently performed the genetic analysis of 102 WD families from a south Indian population, and identified 36 different ATP7B mutations, including 13 novel ones. However, the molecular consequences of these mutations in disease pathology are not known. Using a variety of molecular and cell biology approaches, the interested student(s) will explore and identify the role of these novel ATP7B mutations in disease pathology. The work will also involve the use of specific inhibitor(s) to restore the function of mutated ATP7B, with an aim to develop therapeutic treatment for WD.
- Singh N, Kallollimath P, Shah MH, Kapoor S, Bhat VK, Viswanathan LG, Nagappa M, Bindu PS, Taly AB, Sinha S and Kumar A (2019). Genetic analysis of ATP7B in 102 south Indian families with Wilson disease. PLoS ONE, 14:e0215779.
- Singh N, Bhat VK, Tiwari A, Kodaganur SG, Tontanahal SG, Sarda A, Malini KV and Kumar A (2017). A homozygous mutation in TRIM36 causes autosomal recessive anencephaly in an Indian family. Human Molecular Genetics, 26:1104-1114.
- Pradhan SA, Rather MI, Tiwari A, Bhat VK and Kumar A (2014). Evidence that TSC2 acts as transcription factor and binds to and represses the promoter of epiregulin. Nucleic Acids Research, 42:6243-6255.
- Rather MI, Nagashri MN, Swamy SS, Gopinath KS and Kumar A (2013). Oncogenic microRNA-155 down-regulates tumor suppressor CDC73 and promotes oral squamous cell carcinoma cell proliferation: implications for cancer therapeutics. Journal of Biological Chemistry, 288:608-618.
- Kumar A, Girimaji SC, Duvvari MR and Blanton SH (2009). Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly. American Journal of Human Genetics, 84:286-290.