Abstract
Endocycle is a commonly observed cell cycle variant through which cells undergo repeated rounds of genome DNA replication without mitosis. Endocycling cells arise from mitotic cells through a switch of the cell cycle mode, called the mitotic-to-endocycle switch (MES), to initiate cell growth and terminal differentiation. However, the underlying regulatory mechanisms of MES remain unclear. Here we used the Drosophila steroidogenic organ, called the prothoracic gland (PG), to study regulatory mechanisms of MES, which is critical for the PG to upregulate biosynthesis of the steroid hormone ecdysone. We demonstrate that PG cells undergo MES through downregulation of mitotic cyclins, which is mediated by Fizzy-related (Fzr). Moreover, we performed a RNAi screen to further elucidate the regulatory mechanisms of MES, and identified the evolutionarily conserved chaperonin TCP-1 ring complex (TRiC) as a novel regulator of MES. Knockdown of TRiC subunits in the PG caused a prolonged mitotic period, probably due to impaired nuclear translocation of Fzr, which also caused loss of ecdysteroidogenic activity. These results indicate that TRiC supports proper MES and endocycle progression by regulating Fzr folding. We propose that TRiC-mediated protein quality control is a conserved mechanism supporting MES and endocycling, as well as subsequent terminal differentiation.
Highlights
A tightly controlled cell cycle is a fundamental system for survival in every organism
Endocycling cells arise from proliferating cells through a switch of the cell cycle mode called mitotic-to-endocycle switching (MES)
We used the Drosophila steroidogenic organ to uncover the regulatory factors of MES, and our genetic analyses identified the evolutionarily conserved chaperonin TCP-1 ring complex (TRiC) as a novel regulator of MES and subsequent steroidogenesis
Summary
A tightly controlled cell cycle is a fundamental system for survival in every organism. Endocycle, a cell cycle variant without M phase, is commonly observed in protozoa, plants, and animals [1, 2]. Endocycling cells undergo repeated rounds of S and G phases without a M phase, which gives rise to polyploidy of genome DNA. Endocycle and polyploidy are closely associated with cell growth; in some cell types, progression of endocycling is required for their terminal differentiation [2,3,4]. Polyploid genomic DNA has been observed in approximately 37% of all human tumors [5], and several lines of evidence point to the importance of endocycle in tumor development and survival [6,7,8]. Elucidation of the underlying mechanisms regulating initiation and progression of endocycle is a key step to understanding the role of endocycle in normal and pathological cellular processes
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