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Dr. Maxim Frolov
Professor

  • The Leukemia & Lymphoma Society Scholar
  • Ph.D, Moscow State University, Russia
  • Postdoctoral Fellow: University of Missouri-Columbia, Columbia Massachusetts General Hospital, Harvard Medical School, Boston

Research Interests:
Inappropriate cell proliferation is a hallmark of cancer. In a normal cell, the decision to divide is tightly regulated at multiple levels. However, this control is eroded in cancerous cells, as mutations in tumor suppressor genes remove the checks to restrain proliferation. The research in our laboratory is focused on the retinoblastoma tumor suppressor protein pRB and the E2F transcription factor, which regulates the expression of genes needed for cell proliferation. pRB is a multifunctional protein, but one of its most important roles is to inhibit E2F. Thus, inactivation of pRB, which is considered to be an obligatory event in human cancer, releases the brake from E2F, and unrestrained E2F then drives inappropriate proliferation in tumor cells. However, despite more than 25 years of intensive research, we still do not fully understand all aspects of pRB function and which of the many activities attributed to pRB and E2F are functionally significant in vivo.

The overarching goal of the research in our laboratory is to identify the specific functions of pRB and E2F (called the RB pathway) that are important during normal animal development and why the loss of these functions is one of the key events in cancer. Our laboratory employs biochemical, genetic and genomics approaches to gain mechanistic insights into how the RB pathway regulates cell proliferation and differentiation in vivo. Towards this goal, we are using the simpler Drosophila model system with a streamlined version of the RB pathway. During the past decade, we made several contributions to the field using the fly model.

Cooperation Between RB and Hippo Pathways
We uncovered strong cooperation between the RB and Hippo tumor suppressor pathways. We showed that E2f1 is an important target of Hippo pathway and is required for inappropriate proliferation of Hippo pathway mutants (PLoS Genetics 2008). We discovered that Rb and Hippo pathways maintain the state of terminal differentiation and that their combined inactivation results in dedifferentiation of photoreceptors, which occurs independently of cell proliferation (PLoS Genetics 2010). We showed that E2F and Yki, a downstream effector of Hippo pathway, cooperatively regulate the expression of target genes (Genes & Development 2011). The use of Drosophila, a simpler model system, to dissect cooperation between the Rb and Hippo pathways was valuable because it led to discovery of the mechanism of E2F and Yki cooperation several years before the analogous studies were repeated in mammals. 

Functional Interaction Between Intronic microRNAs and Their Host Genes
While studying the E2f1 gene we noticed that it contains a microRNA cluster within its last intron. Intronic microRNAs are thought to be processed from the same pre-mRNA as host genes and are therefore co-expressed with their host genes. We suggested that such arrangement may result in functional interaction between a microRNA and its host. We developed this idea and showed that mir-11, a microRNA embedded into the E2f1 gene, limits the expression of E2f1 apoptotic targets and this regulation is important during DNA damage induced apoptosis (Genes & Development 2011). This work is significant because this was the first example of an intronic microRNA that directly regulates direct targets of its host gene. We further demonstrated that mir-998, another microRNA embedded into the E2f1 gene, limits E2f1 dependent apoptosis by modulating EGFR pro-survival signaling (PLOS Genetics 2013). Finally, we discovered a novel level of regulation within the mir-11~998 cluster: the expression of miR-998 is absolutely dependent on processing of the adjacent microRNA miR-11 (RNA 2016 and Cell Reports 2017). Notably, approximately half of all microRNAs are embedded into the protein coding genes. Therefore, the concept of functional interaction between an embedded microRNA and its host gene that we proposed is likely to have general applicability beyond the E2f1 gene.

RB Pathway and Cellular Metabolism
A major focus of our recent work is how RB pathway regulates cellular metabolism. We discovered that in Drosophila E2F controls the expression of mitochondria associated genes (Developmental Cell 2013). This regulation is particularly important for triggering apoptosis in response to DNA damage and it helped to explain why irradiation fails to induce apoptosis in E2F deficient animals. We used the results generated in flies to guide our studies in mammalian cells and showed that in a highly analogous manner mammalian E2F controls the expression of mitochondrial genes, which is needed during DNA damage induced apoptosis. This was significant because it linked perturbation of the Rb pathway to changes in cellular metabolism. Recent studies in mice suggested that mitochondrial dysfunction is indeed one of the major consequences of inactivation of Rb pathway. Given that muscles are highly sensitive to mitochondrial dysfunction, we followed up on this initial observation and examined the role of E2F during development of skeletal muscles. This work led to unexpected discovery that E2F directly regulates myogenic differentiation program. Strikingly, this highly specialized role of E2F is, at least, one of the reasons for the lethality of E2F deficient animals since restoration of E2F specifically in skeletal muscles rescues entire E2F mutants to viability (Nature Communications 2016). This is a highly significant result because it challenges the current view of what is the essential function of E2F control in development. Despite E2F being viewed as a cell cycle regulator, our data argue that an essential role of E2F is postmitotic.

Single Cell Genomics
In the past year, we set up a pipeline for single cell genomics (Drop-seq) in the lab to delineate tissue heterogeneity. This platform allows us to individually profile tens of thousands of cells. Our current goals are (i) to build a cell atlas of the developing Drosophila eye, (ii) to uncover the fate of photoreceptors that dedifferentiate following inactivation of RB and Hippo pathways in Drosophila, (iii) to identify the molecular basis of drug resistance in mammalian cells. This platform can be used to understand the source of tumor heterogeneity and therefore could have a great impact on the design of therapeutic strategies.

Selected Publications

Church, V.A., Pressman, S., Isaji, M., Truscott, M., Cizmecioglu, N.T., Buratowski, S., M.V. Frolov and Carthew, R.W. 2017. Microprocessor recruitment to elongating RNA Polymerase II Is required for differential expression of microRNAs. Cell Reports. 20: 3123–3134.

Zappia, M.P. and M.V. Frolov. 2016. E2F function in muscle growth is necessary and sufficient for viability in Drosophila. Nature Communications. 7: 10509.

Ambrus, A.M., A.B. Islam, K.B. Holmes, N.S. Moon, N. Lopez-Bigas, E.V. Benevolenskaya and M.V. Frolov. 2013. Loss of dE2F compromises mitochondrial function. Developmental Cell. 27: 438-451.

Nicolay, B.N., B. Bayarmagnai, A.B. Islam, N. Lopez-Bigas and M.V. Frolov. 2011. Cooperation between dE2F1 and Yki/Sd defines a distinct transcriptional program necessary to bypass cell cycle exit. Genes & Development. 25: 323–335.

Contact

Email: mfrolov@uic.edu
Site:
Office: 312-413-5797
Lab: 312-355-0476

Publications

View Publications on PubMed

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