Regulation of mitosis and morphogenesis in the fungal pathogen Candida albicans

主要研究方向为真核细胞周期进程和形态发生的调控。这些过程中的缺陷对细胞增殖、发育和癌症具有至关重要的意义。我们正在专门研究白色念珠菌有丝分裂和形态发生的调节，这是一种重要的人类真菌病原体。白色念珠菌可以在酵母、假菌丝和极化菌丝细胞之间切换。这种行为对发病机制至关重要；细胞锁定在一种形式，毒性较弱。酵母到菌丝的转换受环境因素的调节，但其机制尚不完全清楚。白色念珠菌对细胞周期和细胞增殖的调控就更不清楚了。我们对白色念珠菌有丝分裂调节因子的研究，包括polo样激酶Cdc5p和后期促进复合体/环小体的激活剂，揭示了与其他真菌相比，白色念珠菌有丝分裂回路中重新连接的独特特征。我们还证明了细胞周期信号深刻地影响形态发生。在酵母中，有丝分裂阻滞导致高度极化的细胞在许多方面与真正的菌丝不同，但在生长后期表达了几个菌丝毒力基因。相反，有丝分裂阻滞通过类似的手段阻止细胞增殖在其他系统。因此，白色念珠菌在有丝分裂过程和形态发生之间显示出一种新的关系，但控制有丝分裂的机制、相关的极性生长和通常受环境信号通路控制的毒力基因的表达仍不清楚。遗传和生化筛选结合分子方法和活细胞成像将用于1)确定白色念珠菌有丝分裂调节因子的作用机制，以获得对细胞增殖控制的见解；2)确定有丝分裂，极化生长和毒力基因激活之间独特关系的机制，以揭示连接这些过程的新电路。我们的工作将对一种重要病原体的细胞增殖、形态发生和毒力的控制、真核细胞周期网络的多样性以及细胞周期和发育之间的相互作用产生新的影响。

My research focuses on the regulation of eukaryotic cell cycle progression and morphogenesis. Defects in these processes have crucial implications for cell proliferation, development, and cancer. We are specifically investigating the regulation of mitosis and morphogenesis in Candida albicans, an important fungal pathogen of humans. C. albicans can switch between yeast, pseudohyphae, and polarized hyphal cells. This behavior is critical for pathogenesis; cells locked in one form loose virulence. The yeast-to-hyphal switch is regulated by environmental cues, but the mechanisms are not fully understood. Regulation of the cell cycle and cell proliferation in C. albicans is even less clear. Our work on mitotic regulators in C. albicans, including the polo-like kinase Cdc5p, and activators of the Anaphase Promoting Complex/ Cyclosome, revealed distinct features compared to other fungi that suggest re-wiring in the mitotic circuitry. We also demonstrated that cell cycle signals profoundly influence morphogenesis. Mitotic arrest in yeast resulted in highly polarized cells that were distinct from true hyphae in may respects, yet expressed several hyphal virulence genes at later growth stages. In contrast, mitotic arrest through similar means prevents cell proliferation in other systems. Thus, C. albicans shows a novel relationship between mitotic progression and morphogenesis, but the mechanisms controlling mitosis, associated polar growth and expression of virulence genes normally under control of environmental signaling pathways remain unclear. Genetic and biochemical screens coupled with molecular approaches and live cell imaging will be utilized to 1) define the mechanisms of action of mitotic regulators in C. albicans, in order to gain insights on the control of cell proliferation; and 2) determine the mechanisms underlying the distinct relationship between mitosis, polarized growth and activation of virulence genes, in order to uncover novel circuitry linking these processes. Our work will have novel implications for the control of cell proliferation, morphogenesis, and virulence in an important pathogen, the diversity in eukaryotic cell cycle networks, and the interplay between the cell cycle and development.