Cell cycle is required by both unicellular and multicellular organisms to transmit their genetic information. It is well known that the major regulatory mechanism of eukaryotic cell cycle is determined by cyclin-dependent kinases (CDKs) and their cyclin partners. On the other hand, an increasing number of studies have shown that the regulation of cell cycle is quite subtle involving many factors. Research papers in this issue provide new insights into the regulation of cell cycle.

Mitosis is an energy-cost process, in which homologous chromosomes have to be segregated and moved into two daughter cells. However, the metabolic regulation during distinct mitotic phases is poorly understood so far. Dr Zang and colleagues reported that AMP-activated protein kinase (AMPK), an important regulator of cellular energy homeostasis, is involved throughout cell division, with AMPK catalytic subunits associated with separate mitotic apparatus. In particular, the authors showed that AMPK could phosphorylate an amino acid residue Ser801 of KIF4A, a chromosome-associated kinesin, and resulted in the regulation of anaphase central spindle length. This work, for the first time, shows the link between the energy sensor AMPK and mitotic apparatus control.

In the next paper, Dr Shi and colleagues reported a new regulatory mechanism for the control of chromosome segregation in mitosis. The authors solved the complex structure of the small GTPase Ran with the nucleotide release factor Mog1 and further revealed that Mog1 competed with RCC1, a Ran regulator, for Ran binding in a GTP/GDP-dependent manner. In addition, they found that Ran could be acetylated by the acetyltransferase TIP60, which resulted in the liberation of Mog1 from Ran binding during mitosis. Importantly, this acetylation-based switch of Ran binding to RCC1 enhanced the Ran-GTP level, which is essential for chromosome alignment.

In addition to cyclins that bind to and activate CDKs, a number of CDK inhibitors such as p16INK, p19ARF, and p21CIP have also been found to negatively regulate cell cycle. Dr Knauer and colleagues reported a new regulatory mechanism for transcriptional programs of these CDK inhibitors. The authors showed that the transcription factor TFIIA was regulated by a ‘cleave-and-run’ switch including interaction with the nuclear export receptor Crm1/Exportin-1 and subsequent proteolytic cleavage by the protease Taspase 1. The inhibition of TFIIA proteolysis and nuclear export promoted the TFIIA−TATA box binding protein (TBP) complex formation, resulting in the upregulation of the cell cycle inhibitor p16INK.

Dys-regulation of cell cycle often generates tumorigenesis. In order to reveal the regulatory role of TGF-β in the proliferation of hepatocellular carcinoma (HCC), Drs Yan and Chen’s groups identified a novel TGF-β target gene, CXXC5, and analyzed its role in the control of HCC cell cycle. The authors showed that knockdown of CXXC5 reduced the expression of TGF-β target genes and then relieved TGF-β-induced growth inhibition of HCC cells. They further revealed that CXXC5 could bind to the histone deacetylase HDAC1, disrupting the interaction between HDAC1 and Smad2/3 to abolish the inhibitory effect of HDAC1 on TGF-β signaling. Their work suggests that CXXC5 may act as a tumor suppressor by promoting TGF-β signaling via a positive feedback loop.