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Hyaluronan mediated motility receptor regulates daughter cell size control pathways during mitosis Mei, Lin


During cell division, one mitotic cell generates two daughter cells. Molecular pathways that build, stabilize and orient the mitotic spindle are critical during cell division as the mitotic spindle ensures equal segregation of chromosomes and controls the size of the daughter cells. During anaphase, the spindle mid-zone signals the cleavage site, a site that defines the separation of the daughter cells in most animal cells. Under normal conditions, the spindle is centred in the dividing cell, leading to equal-sized daughter cells. However, daughter cells with different physical sizes can be generated due to an off-centre spindle during anaphase. Unequal-sized daughter cells differ in their relative amounts of cytoplasmic content, such as organelles, which can affect their survival, growth, and behavior. Several mechanisms regulate daughter cell size in mitosis, including asymmetric cortical dynein pulling forces on the spindle and asymmetric membrane elongation at the cell surface. The Maxwell Lab revealed that the gene product hyaluronan mediated motility receptor (HMMR) plays an important role in the asymmetric cortical localization and activity of dynein, a pulling-force generating microtubule motor protein. Moreover, HMMR is a breast cancer susceptibility gene. My research now shows that HMMR also regulates asymmetric membrane elongation to control daughter cell size. My results reveal that HMMR-overexpressing cells display ectopic membrane elongation at anaphase as well as the ultimate loss of daughter cell size control; moreover, elevated HMMR expression correlates with activation of Aurora kinase A and mis-localization of components of the ARP2/3 complex, which potentially disrupts the stability of the cortex during mitosis. Collectively, my research identifies a new role for HMMR in the regulation of cortical integrity and daughter cell sizes potentially through an Aurora kinase A-dependent control of ARP2/3 complex localization to the mitotic spindle poles. The disruption of daughter cell size control mediated by elevated HMMR expression may contribute to heterogeneous cell size and genome instability that often occurs during tumorigenesis.

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