Regulation of cell growth in multicellular organisms.

Research

Growth regulation in multicellular organisms

Cell growth occurs as cells increase their biomass and/or divide. However, the mechanisms of cell growth particularly in multicellular organisms are incompletely understood. The aim of my laboratory is to utilize genome-scale approaches to understand growth regulation at the cellular level. Previous work has identified several hundred genes in Drosophila cells whose loss-of-function results in changes in cell growth and division [1]. Systematic and unbiased approaches in Drosophila[1] and mammalian[2] cell models are further used in order to identify and refine mechanisms responsible for cell proliferation and cell size control. Importantly, these mechanisms are often misregulated in cancer and are also affected in metabolic diseases such as type II diabetes.

We are particularly interested in elucidating the mechanisms of growth control that occur post transcriptionally. These include the effects of microRNAs and mRNA deadenylases on mRNA levels as well as the effects of protein kinases and phosphatases on proteins. A further aim of the work in the laboratory is to decipher how these post-transcriptional events are affected by nutrient levels and the metabolic state of the cell.

Figure. (A) Although cell growth can be separated conceptually into increase in cell size and increase in cell number through cell division, these two are highly connected processes. Cells continue to grow as they go through the cell cycle and cells in G1 phase of the cell cycle are smaller than G2 cells with twice as much DNA. The knock-down of some genes such as cdc2 and ubiquitin by RNAi (red circles) results in specific increase in cell size in G2/M phase of the cell cycle as measured by flow cytometry. Thus, cells are able to continue their growth even if their cell cycle progression is blocked, for example by the loss-of cdc2 kinase. However, cell growth in general appears to occur at comparable rates in both G1 and G2 phases of the cell cycle.

Figure (B) A schematic drawing of the information flow with some of the regulatory steps highlighted. In reality, growth is regulated at all levels with multiple mechanisms sending feedback information to previous steps.

Teaching

Publications

1. Björklund M, Taipale M, Varjosalo M, Lahdenperä J, Saharinen J and Taipale J. Identification of pathways required for cell growth and proliferation by RNAi. Nature, 439:1009-13, 2006.

2. Varjosalo M, Björklund M, Cheng F, Syvänen H, Kivioja T, Kilpinen S, Sun Z, Kallioniemi O, Stunnenberg HG, He WW, Ojala P and Taipale J. Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling. Cell, 133:537-48, 2008.

3. Tuupanen S, Turunen M, Lehtonen R, Hallikas O, Vanharanta S, Kivioja T, Björklund M, Wei G, Yan J, Niittymäki I, Mecklin JP, Järvinen H, Ristimäki A, Di-Bernardo M, East P, Carvajal-Carmona L, Houlston RS, Tomlinson I, Palin K, Ukkonen E, Karhu A, Taipale J and Aaltonen LA. The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. Nat Genet. 41:885-90, 2009.