Laboratory of Larisa Litovchick, M.D., Ph.D.
Dr. Litovchick’s laboratory studies the mechanisms that control cell proliferation. The ability of cells to halt proliferation and to enter quiescent state is important for embryonic development, maintaining the tissue and organ size as well as for tumor suppression. On the other hand, the ability of cells to leave quiescent state and to resume proliferation is critical for stem cell function and tissue regeneration. Understanding the mechanisms of transition from proliferation to quiescence and back will help us to harness these processes for improving of the human health.
Cellular quiescence is regulated by multiple cellular pathways that converge on key factors such as RB family of proteins pRB, p107 and p130. Upon entry into quiescence, p130 is recruited into the DREAM transcriptional repressor complex that controls >800 cell cycle-regulated genes. The recruitment of p130 requires phosphorylation of LIN52 subunit of the DREAM by DYRK1A protein kinase. DYRK1A gene is known to play an essential role in neurological development and it is mapped to a Down syndrome critical region on chromosome 21.
Previous research by Dr. Litovchick implicates DYRK1A into tumor suppression. Indeed, DYRK1A phosphorylation of the DREAM is important for entry into quiescence as well as for oncogenic Ras-induced senescence, a protective mechanisms that suppresses malignant transformation. Furthermore, oncogenomic data mining reveals frequent loss of heterozygosity of the DYRK1A gene in high-grade ovarian carcinomas, the most lethal type of cancer in women. Therefore, Dr. Litovchick’s lab is using cell-based transformation models for characterizing oncogenic pathways that could cooperate with inactivation of DYRK1A in ovarian carcinogenesis. One of the signaling pathways known to contribute to cell proliferation and invasion in ovarian cancer relies on bioactive lipid-mediated signaling. In collaboration with Dr. F. Fang (Department of Biochemistry and Molecular Biology, VCU), Litovchick’s lab is investigating the effects of the lipid signaling on DYRK1A activity and the DREAM complex function.
Despite the important physiological role of DYRK1A, the upstream regulators and the downstream effectors of this protein kinase in the cells are not well characterized. To understand the function of DYRK1A, Dr. Litovchick’s lab is characterizing DYRK1A-interacting proteins in human cells identified by proteomic analysis in collaboration with Dr. Michael Washburn from the Stowers Institute for Biomedical Research and Dr. James DeCaprio from Dana-Farber Cancer Institute. This analysis identified a known DYRK1A-binding protein DCAF7 as well as several new protein: protein interactions that implicate DYRK1A into the processes of DNA damage response, regulation of transcription and cell growth. The functional and biochemical characterization of these novel DYRK1A-interacting proteins that is currently underway.
Knowledge obtained in these studies will help to understand the functions and regulation of DYRK1A deregulation of which could contribute to cancer and the Down syndrome pathogenesis. From translational perspective, it will be interesting to determine whether the tumors with impaired function of DYRK1A or the DREAM complex could have increased sensitivity to specific anti-cancer drugs. Induction of cancer cell quiescence by cytotoxic chemotherapy is one of the mechanisms that contribute to the chemoresistance of tumors.
Vijay Menon, Ph.D.
Siddharth Saini, PhD
A Systematic Analysis of Negative Growth Control Implicates the DREAM Complex in Cancer Cell Dormancy. MacDonald J, Ramos-Valdes Y, Perampalam P, Litovchick L, DiMattia GE, Dick FA. Mol Cancer Res. 2017 Apr;15(4):371-381. doi: 10.1158/1541-7786.MCR-16-0323-T. Epub 2016 Dec 28. PMID: 28031411
Litovchick L, Florens LA, Swanson SK, Washburn MP, DeCaprio JA. DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev. 2011 Apr 15;25(8):801-13.
Litovchick L, Sadasivam S, Florens L, Zhu X, Swanson SK, Velmurugan S, Chen R, Washburn MP, Liu XS, DeCaprio JA. Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence. Mol Cell. 2007 May 25;26(4):539-51.