Yeast Cip1 is activated by environmental stress to inhibit Cdk1–G1 cyclins via Mcm1 and Msn2/4

Abstract

Upon environmental changes, proliferating cells delay cell cycle to prevent further damage accumulation. Yeast Cip1 is a Cdk1 and Cln2-associated protein. However, the function and regulation of Cip1 are still poorly understood. Here we report that Cip1 expression is co-regulated by the cell-cycle-mediated factor Mcm1 and the stress-mediated factors Msn2/4. Overexpression of Cip1 arrests cell cycle through inhibition of Cdk1–G1 cyclin complexes at G1 stage and the stress-activated protein kinase-dependent Cip1 T65, T69, and T73 phosphorylation may strengthen the Cip1and Cdk1–G1 cyclin interaction. Cip1 accumulation mainly targets Cdk1–Cln3 complex to prevent Whi5 phosphorylation and inhibit early G1 progression. Under osmotic stress, Cip1 expression triggers transient G1 delay which plays a functionally redundant role with another hyperosmolar activated CKI, Sic1. These findings indicate that Cip1 functions similarly to mammalian p21 as a stress-induced CDK inhibitor to decelerate cell cycle through G1 cyclins to cope with environmental stresses.

The coordinate actions of calcineurin and Hog1 mediate the response to cellular stress through multiple nodes of the cell cycle network

“…Our data suggests that this G1/S arrest occurs through crosstalk to the Hog1 pathway, since downregulation of SBF/MBF target genes and initial cell cycle arrest do not occur in hog1D cells. This Hog1-dependent arrest likely occurs through a combination of its effect on transcription and its ability to upregulate Cdk1 inhibitors, as previously described (Bellí et al, 2001;Chang et al, 2017;Escoté et al, 2004;González-Novo et al, 2015).…”

“…In budding yeast, the stress-activated MAPK Hog1 has two roles in controlling entry into S phase. Hog1 both inhibits the SBF and MBF TF complexes that drive expression of G1/S genes (Bellí et al, 2001;González-Novo et al, 2015), and increases levels of the Cdk1 inhibitors Sic1 and Cip1, which inhibit G1 cyclin/Cdk complexes and block entry into S phase (Chang et al, 2017;Escoté et al, 2004).…”

Cg Hog1-Mediated Cg Rds2 Phosphorylation Alters Glycerophospholipid Composition To Coordinate Osmotic Stress in Candida glabrata

“…CgHog1 interacts with CgRds2 under osmotic stress. Hog1, a protein kinase of the HOG pathway, is known to be essential for cell survival by rapidly activating a number of downstream genes under osmotic stress (2,14). Thus, we wondered whether there was a relationship between CgHog1 and CgRds2 at 1.5 M NaCl.…”

“…To further identify the phosphorylation site(s) for CgHog1 in CgRds2, we investigated four sequences corresponding to the consensus phosphorylation sites for CgHog1 (Ser-Pro or Thr-Pro) (2,17,35) in the CgRds2 protein (Ser64, Thr97, Thr238, and Ser455) ( Fig. S2).…”

“…Recent studies have also identified additional proteins phosphorylated by Hog1 to coordinate the metabolic pathway under stress conditions. For example, yeast Cip1 was shown to be phosphorylated by Hog1 to inhibit Cdk1-G 1 cyclins, resulting in cell cycle delay (2). The Hog1-mediated phosphorylation of Mrc1 protein was found to protect genomic integrity through preventing conflicts between DNA replication and transcription (35).…”