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Growth Control and Cancer GeneticsUsing fruit fly, zebrafish and mammalian cells as our experimental models, our main research goal is to understand how tissue growth and organ size are normally regulated during animal development and how disruption of such regulation can lead to cancer development. In recent years, a growth inhibitory pathway mediated by tumor suppressors such as Hippo and Warts (Wts)/Lats protein kinases has been found to be critical for tissue growth and organ size control. In 2005, my laboratory discovered a novel component of this pathway, Mob as tumor suppressor (Mats) (Lai et al., Cell 2005). Mats functions as a coactivator of Wts kinase, and Mats function is conserved in evolution. Moreover, we found that Mats is a target of Hippo kinase. Mats phosphorylation by Hippo increases its affinity with Wts/Lats and ability to increase Wts catalytic activity to target a key downstream oncogeneic protein Yorkie (Yki). Importantly, the mechanism by which Mats is activated by Hippo via phosphorylation is conserved from flies to human (Wei et al., EMBOJ 2007). Our discovery of the mats gene family has led us into studies using zebrafish, mice and human cells. Some ongoing research projects are described below. (1). Most of our current knowledge about Hippo signaling has come from studies in Drosophila. It is not clear how Hippo pathway components in mammals such as human might function to regulate tissues growth. In collaboration with Dr. K.-L. Guan’s laboratory at UC San Diego, a human oncoprotein YAP (a human homolog of fly Yki) has been investigated. It turned out that Lats/Mats-mediated phosphorylation and cytoplamic localization is critical for YAP inhibition in controlling tissue growth and cell contact inhibition. This is the first time that Hippo signaling is shown to mediate growth inhibition by targeting YAP oncoprotein in mammals (Zhao et al., Genes & Dev. 2007). Moreover, transcription coactivator Yki was found to function as a binding partner with a DNA-binding transcription factor Scalloped (Sd) to control cell number and tissue growth. Similarly, human YAP works with TEAD family of transcription factors (human Sd proteins) to regulate target gene expression to induce cell growth and epithelial-mesenchymal transition (Zhao et al., Genes & Dev. 2008). Thus, as newly identified components in the Hippo pathway, Sd/TEAD and Yki/YAP proteins function together to promote tissue growth by regulating target gene transcription. These studies support a model that defective Hippo signaling leads to human cancer development. (2). We have used zebrafish as a model to test a hypothesis that the function of mats as a growth regulator is evolutionarily conserved in vertebrate animals. Through a morpholino-based knockdown approach, we found that mats1 plays a critical role during zebrafish early development as mats1 morphant embryos exhibited severe developmental delay similar to that of Drosophila homozygous mats mutants. This abnormal phenotype was mainly caused by defective cell proliferation and apoptosis. Interestingly, mats1 morphant cells proliferate faster than normal cells in chimeric embryos similar to what was observed in Drosophila mats mosaic individuals. These results support the idea that the growth regulatory function of mats genes is conserved during evolution. (3). In collaboration with Dr. M. Nei’s laboratory, we have done a molecular evolutionary analysis of the mob genes and found that the mob gene family is a molecular innovation of eukaryotes. From an initial mob ancestor, three duplications occurred very early to generate four groups of mob genes, which continue to exist in most eukaryotes today. This analysis revealed the evolutionary history of mob gene family and shall help functional studies of Mob family proteins.Photoreceptor Cell Fate DeterminationSignaling pathways that involve two receptor tyrosine kinases (Drosophila homolg of EGF receptor and Sevenless) are responsible for transmitting developmental signals to determine cell fates in the eye. However, inhibitory regulation that is required to control cellular competence to respond to inductive signals is less understood. Our research is focused on two nuclear proteins encoded by the yan and tramtrack (ttk) genes. Loss of the yan or ttk function results in the differentiation of ectopic photoreceptors. yan encodes an ETS DNA-binding protein and ttk encodes two zinc-finger proteins. In the presumptive R7 photoreceptor cells, both yan and ttk appear to act antagonistically to the proneural signal mediated by sevenless and Ras1. Moreover, yan and ttk synergistically interact to inhibit the formation of R7 cells. Thus, yan and ttk constitute of a negative nuclear regulatory system that maintains precursor cells in an undifferentiated state until they receive positive signaling, for example, the sevenless-mediated signaling for the development of R7 neuron. An unsolved question is how such inhibitory system is established in precursor cells. To investigate this issue, we are examining yan expression in some mutant background. It is possible that Notch signaling is responsible for the induction of yan expression. We are also currently trying to identify regulatory sequences that can specify yan expression in the developing eye by using a transgenic approach. Neural MorphogenesisConstruction of a functional organ such as eye requires not only specification of many different cell types, but also proper assembly of these cells in a highly ordered manner. Our preliminary work demonstrated that the delayed furrow (defu) gene can be a critical regulator of eye morphogenesis. Removal of the defu gene activity results in failure of proper spacing between developing unit eyes and coordinated sequences of unit eye assembly. Our ongoing research is aimed at molecular genetic characterization of the defu gene. Future directions of this project include biochemical and evolutionary studies of the defu gene.
Representative Publications:
Search the MEDLINE database at PubMed for articles by Z.-C. Lai |
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