Cell size checkpoint control by the retinoblastoma tumor suppressor pathway
Cell size checkpoint control by the retinoblastoma tumor suppressor pathway
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DOI：
10.1371/journal.pgen.0020167
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发表时间：
2006-10-01
期刊：
影响因子：
4.5
通讯作者：
Umen, James G.
中科院分区：
文献类型：
--
作者：
Fang, Su-Chiung;de los Reyes, Chris;Umen, James G.
大小控制对于所有增殖细胞都是必不可少的，并且被认为是通过将细胞大小与细胞周期进程相结合的检查点来调节的。视网膜母细胞瘤（RB）肿瘤抑制途径突变引起的异常细胞大小表型与大小检查点控制中的作用一致，但难以排除细胞周期动力学改变引起的对大小的间接影响。单细胞莱茵衣原体的多分裂细胞周期将生长与分裂分开，从而可以直接评估大小表型和检查点功能之间的关系。C.由MAT 3编码的莱茵衣藻RB同源物引起超多的细胞分裂和小细胞，表明MAT 3在大小控制中的作用。我们确定了一个mat3无效等位基因的抑制基因，该等位基因在DP1中具有隐性突变或在E2F1中具有显性突变，该基因座编码RB相关蛋白靶向的异源二聚体转录因子的同源物。值得注意的是，我们确定dp1和e2f1表型是由大小检查点控制缺陷引起的，而不是由于细胞周期延长。尽管他们的细胞分裂缺陷，马特3，dp1，和e2f1突变体表现出几乎没有变化，在S期和有丝分裂，其中许多是保守的RB途径的目标诱导的基因的周期性转录。相反，我们发现，当S期和有丝分裂转录被抑制时，细胞大小的调节不受影响。我们的数据提供了直接的证据，RB途径介导的细胞大小检查点控制，并建议这种控制是不直接耦合到周期性细胞周期转录的幅度。
Size control is essential for all proliferating cells, and is thought to be regulated by checkpoints that couple cell size to cell cycle progression. The aberrant cell-size phenotypes caused by mutations in the retinoblastoma (RB) tumor suppressor pathway are consistent with a role in size checkpoint control, but indirect effects on size caused by altered cell cycle kinetics are difficult to rule out. The multiple fission cell cycle of the unicellular alga Chlamydomonas reinhardtii uncouples growth from division, allowing direct assessment of the relationship between size phenotypes and checkpoint function. Mutations in the C. reinhardtii RB homolog encoded by MAT3 cause supernumerous cell divisions and small cells, suggesting a role for MAT3 in size control. We identified suppressors of an mat3 null allele that had recessive mutations in DP1 or dominant mutations in E2F1, loci encoding homologs of a heterodimeric transcription factor that is targeted by RB-related proteins. Significantly, we determined that the dp1 and e2f1 phenotypes were caused by defects in size checkpoint control and were not due to a lengthened cell cycle. Despite their cell division defects, mat3, dp1, and e2f1 mutants showed almost no changes in periodic transcription of genes induced during S phase and mitosis, many of which are conserved targets of the RB pathway. Conversely, we found that regulation of cell size was unaffected when S phase and mitotic transcription were inhibited. Our data provide direct evidence that the RB pathway mediates cell size checkpoint control and suggest that such control is not directly coupled to the magnitude of periodic cell cycle transcription.