Mollinedo F, Gajate C
Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
Apoptosis. 2003 Oct;8(5):413-50. doi: 10.1023/a:1025513106330.
Microtubules are dynamic polymers that play crucial roles in a large number of cellular functions. Their pivotal role in mitosis makes them a target for the development of anticancer drugs. Microtubule-damaging agents suppress microtubule dynamics, leading to disruption of the mitotic spindle in dividing cells, cell cycle arrest at M phase, and late apoptosis. A better understanding of the processes coupling microtubule damage to the onset of apoptosis will reveal sites of potential intervention in cancer chemotherapy. Inhibition of microtubule dynamics induces persistent modification of biological processes (M arrest) and signaling pathways (mitotic spindle assembly checkpoint activation, Bcl-2 phosphorylation, c-Jun NH(2)-terminal kinase activation), which ultimately lead to apoptosis through the accumulation of signals that finally reach the threshold for the onset of apoptosis or through diminishing the threshold for engagement of cell death. Microtubules serve also as scaffolds for signaling molecules that regulate apoptosis, such as Bim and survivin, and their release from microtubules affect the activities of these apoptosis regulators. Thus, sustained modification of signaling routes and changes in the scaffolding properties of microtubules seem to constitute two major processes in the apoptotic response induced by microtubule-interfering agents.
微管是动态聚合物，在大量细胞功能中发挥关键作用。它们在有丝分裂中的关键作用使其成为抗癌药物开发的靶点。微管损伤剂抑制微管动力学，导致分裂细胞中的有丝分裂纺锤体破坏、细胞周期在M期停滞以及晚期凋亡。更好地理解将微管损伤与凋亡起始相耦合的过程，将揭示癌症化疗中潜在的干预位点。微管动力学的抑制会诱导生物过程（M期停滞）和信号通路（有丝分裂纺锤体组装检查点激活、Bcl-2磷酸化、c-Jun氨基末端激酶激活）的持续改变，这些最终通过积累最终达到凋亡起始阈值的信号或通过降低细胞死亡参与阈值而导致凋亡。微管还作为调节凋亡的信号分子（如Bim和survivin）的支架，它们从微管上的释放会影响这些凋亡调节因子的活性。因此，信号通路的持续改变和微管支架特性的变化似乎构成了微管干扰剂诱导的凋亡反应中的两个主要过程。
