Cell Polarity and Cytokinesis

 描述(由申请人提供)：细胞质分裂和细胞极性的缺陷都与癌症等人类疾病有关，但它们之间可能的因果联系尚不清楚。胞质分裂是一个细胞分裂成两个细胞，通过构建一个由丝状肌动蛋白和肌球蛋白II组成的收缩环来完成。当两个子细胞接受相同的细胞质和皮质成分并继承相同的细胞命运时，这种分裂被称为对称分裂。然而，在许多特殊的细胞分裂中，例如在胚胎发育和干细胞中，分裂是不对称的，导致子代细胞具有不同的细胞命运和/或不同的大小。在动物细胞中，不对称分裂由PAR蛋白(分裂缺陷)控制，PAR蛋白定位于细胞皮质，确保每个子细胞接收适当的细胞命运决定因素。PAR蛋白被认为通过决定有丝分裂纺锤体的位置和方向来间接调节细胞的不对称分裂，然后有丝分裂纺锤体定位肌球蛋白收缩环来驱动细胞分裂。然而，我们的初步数据表明，PAR蛋白还通过增加收缩环组装和收缩的健壮性直接促进细胞质分裂。在……里面 在线虫受精卵中，PAR蛋白定位于不同的前部(APARs)和后部(PPAR)皮质和细胞质区域，建立前后轴。我们发现，在收缩环减弱的突变体中，皮层aPAR或PPAR的缺失增加了细胞质分裂失败率。此外，我们发现PAR蛋白促进了丝状肌动蛋白和肌球蛋白-II向收缩环的募集。基于这些数据，我们的中心假设是，PAR蛋白通过促进收缩环收缩的健壮性来防止细胞质分裂失败。在这项建议中，我们将通过三种方式确定介导这种针对细胞质分裂失败的保护的分子机制：1)我们将确定保护细胞质分裂所需的极性机制(PAR蛋白和PAR相互作用蛋白)的特定分子成分；2)我们将确定PAR蛋白保护细胞质分裂失败的细胞机制(S)；以及3)我们将确定PAR蛋白是否在多细胞环境下的胚胎发生过程中保护细胞质分裂。由于细胞质分裂失败和细胞极性失调都受到进化上保守的分子机制的调控，而且两者都正在成为人类疾病(如癌症)的生物标志物，因此我们的工作将与人类健康相关。

 DESCRIPTION (provided by applicant): Defects in both cytokinesis and cell polarity are associated with human disease such as cancer but the possible causal link between them remains unknown. Cytokinesis is the physical division of one cell into two, accomplished by the construction of a contractile ring composed of filamentous actin and the motor myosin-II. When the two daughter cells receive the same cytoplasmic and cortical components and inherit the same cell fate, the division is referred to as symmetric. However, in many specialized cell divisions, such as during embryogenesis and in stem cells, division is asymmetric, resulting in daughter cells with different cell fates and/or of different sizes. In animal cells, asymmetric division is controlled by the PAR proteins (PARtitioning defective), which localize to the cell cortex and ensure each daughter cell receives the proper cell fate determinants. The PAR proteins are thought to regulate asymmetric cell division indirectly by dictating the position and orientation of the mitotic spindle, which then positions the actomyosin contractile ring to drive cell division. However, our preliminary data suggests that the PAR proteins also promote cytokinesis directly by increasing the robustness of contractile ring assembly and constriction. In the C. elegans zygote, the PAR proteins localize to distinct anterior (aPARs) and posterior (pPARs) cortical and cytoplasmic domains to establish the anterior-posterior axis. We found that loss of either the cortical aPARs or pPARs enhanced the cytokinesis failure rate in mutants with weakened contractile rings. Further, we found that the PAR proteins promote the recruitment of filamentous actin and myosin-II to the contractile ring. Based on these data, our central hypothesis is that the PAR proteins protect against cytokinesis failure by contributing to the robustness of contractile ring constriction. In this proposal, we will determine the molecular mechanisms that mediate this protection against cytokinesis failure in three ways: 1) We will identify the specific molecular components of the polarity machinery (PAR proteins and PAR interacting proteins) that are required for cytokinesis protection; 2) we will determine the cellulr mechanism(s) of protection from cytokinesis failure by the PAR proteins; and 3) we will determine if PAR proteins play a more general role in protecting cytokinesis during embryogenesis in a multicellular context. As both cytokinesis failure and dysregulation of cell polarity are regulated by evolutionarily conserved molecular mechanisms and both are emerging as biomarkers for human diseases such as cancer, our work will have relevance for human health.