Cellular metabolism is tightly coordinated with the needs of the existing cellular state. Dividing cells must duplicate their cellular components and synthesize large amounts of proteins, lipids and DNA. Yet how metabolic processes are regulated to efficiently generate this material needed for cell division –– is only beginning to be understood. Authors [see the exciting attached full article + editorial] now reveal a direct link between regulation of the cell cycle and that of cell metabolism. Cyclin-Dependent Kinases (CDKs) comprise a family of five mammalian protein kinases, known for participation in regulating the cell cycle. They are also known to participate in transcription regulation, mRNA-processing, and differentiation during neurogenesis. CDKs are so highly conserved that yeast cells can divide normally when the human homolog is replaced with the yeast Cdk gene product..!!
D-type cyclin proteins and their catalytic binding-partner enzyme –– either one of the cyclin-dependent kinases CDK4 or CDK6 –– are required for cell division. They exhibit peak activity during the early cell-cycle stage known as the G1 phase, when the cell grows in size and synthesizes components needed for DNA replication and cell division. The protein retinoblastoma (RB1 is among the most extensively studied substrates of the cyclin D–CDK complex. Progression through G1 requires the action of E2F transcription factors. (There are eight E2F genes in the mammalian genome, further complicating this story.) However, activity of E2F proteins is blocked when they bind to RB1. Phosphorylation of RB1 by the cyclin D–CDK complex releases E2F proteins from their inhibitory interaction with RB1, enabling cell-cycle progression from G1 into the S phase. In cancer cells, inhibition of CDK4 and CDK6 commonly causes cell-cycle arrest –– mostly because the RB1–E2F complex is stabilized. Some cancer cells die when treated with inhibitors of CDK4 and CDK6.
Investigating human tumor cells grown in culture, authors found that CDK6 inhibition induces death of cells that predominantly use the combination of cyclin D3 and CDK6. Surprisingly, they discovered that this cell death did not require presence of RB1. Authors therefore investigated how inhibition of CDK6 resultsin cell death that is independent of the role of RB1 in cell-cycle regulation. They searched for CDK targets that might be relevant to this process by looking for proteins that associate with the cyclin–CDK complex. This led to identification of the enzymes phosphofructokinase-1 (PFK1) and pyruvate kinase-M2 (PKM2). Authors showed that these proteins are directly phosphorylated –– by a complex formed of the specific combination of cyclin D3 and CDK6.
PFK1 and PKM2 each exist in both dimeric and tetrameric forms, with tetrameric forms being more active. Tests to investigate the effect of phosphorylation of these enzymes gave results consistent with a model in which phosphorylation inhibits PFK1 and PKM2 activities by decreasing formation of tetramers in favor of the less-active dimers. PFK1 and PKM2 are well known to function in glycolysis –– a key metabolic pathway that breaks down glucose through a series of intermediates, to generate the molecule pyruvate. Diminishing PFK1 and PKM2 activities results in the accumulation of glycolytic intermediates; if this occurs, rather than progressing through glycolysis to give pyruvate, these intermediates can feed into metabolic pathways known as the pentose phosphate pathway (PPP) and the serine synthesis pathway. The former yields the carbohydrate ribose, and the latter the amino acids serine and glycine –– all of which are important substrates for nucleotide synthesis. The two pathways also generate cofactor NADPH and the antioxidant peptide reduced glutathione (GSH), both of which are able to neutralize reactive oxygen species (ROS). Further insight into connection points between the cell cycle and metabolism might pave the way for development of successful cancer therapies that can target such metabolic vulnerabilities of tumor cells.
Nature 15 June 2o17; 546: 426–430 (full article) and 357–358 (News-N-Views)