Cyclin-dependent kinases regulate Hif1? to promote cell-cycle progression

Hypoxia-inducible factor 1 (HIF-1) is regulated by cellular O2 availability through O2-dependent hydroxylation reactions. Under hypoxic conditions, stability of HIF-1? increased, thus improving binding of co-activators, and increasing transcription of HIF-1 target genes. In addition to proteasome-dependent pathways for HIF-1? degradation, here, we identified a pathway by which HIF-1? can be targeted for lysosomal degradation through chaperone-mediated autophagy.

Firstly, we found that there are physically and functionally interaction between HIF-1? and cyclin-dependent kinase 1 (Cdk1) and Cdk2. Cells transfected with wild-type Cdk1 showed increased induction of HIF-1? upon exposure to hypoxia, comparing with cells transfected with kinase dead mutant.

Next, we use luciferase assay to demonstrate that HIF1a transcriptional activity is increased upon Cdk1 over expression. Besides, we use inhibitors, which can block proteasome and lysosome to show that regulation of HIF-1? by Cdk1 is proteasome-independent and lysosome-dependent.

In conclusion, this work reveal that HIF-1? levels are coupled to phases of the cell cycle through lysosomal degradation and identify a novel role for the lysosome as a regulator of cell-cycle progression under hypoxic conditions. This may be helpful in use of Cdk1 inhibitors in tumors with high levels of HIF-1?.

The nucleosome is the basic unit of DNA packaging, consisting of DNA and eight histone protein cores. H4 is just one of them. Modifications on histone tail may change the density of chromatin, thus regulating transcription machinery proteins, and control gene expression. Here, we report histone H4 tail regulate nucleosome remodeling.

H4 tail acetylation associated with transcriptionally active chromatin is thought to help prevent ISWI-induced nucleosome spacing at actively transcribed genes. We reconstituted mono-nucleosomes with varying linker lengths to answer the question of linker DNA regulates nucleosome translocation. The catalytic subunits of ISWI enzymes possess an SF2-like ATPase.

The AutoN domain of Snf2h and the nucleosomal H4 tail are important for linker DNA length sensing by the ACF complex. Finally, we tested the physiological importance of the N-terminal region of Acf1 by studying the role of its homologue in yeast. When the linker DNA is short, Acf1 preferentially binds to the H4 tail, and the ATPase activity is inhibited by AutoN. When the linker DNA length increases, Acf1 shifts its binding preference to the linker DNA, allowing it to activate ACF.

Taken together, our results suggest a nucleosome-spacing mechanism for ACF in which the linker DNA length is sensed by the Acf1 accessory subunit and allosterically transmitted to the Snf2h catalytic subunit through the H4 tail of the nucleosome

Numerologist Warda is hooked on OG-L002 fishing, collecting. And lastly her encouragement comes from socializing along with her companions.