An essential role for Ink4 and Cip/Kip cell-cycle inhibitors in preventing replicative stress

Abstract

Cell-cycle inhibitors of the Ink4 and Cip/Kip families are involved in cellular senescence and tumor suppression. These inhibitors are individually dispensable for the cell cycle and inactivation of specific family members results in increased proliferation and enhanced susceptibility to tumor development. We have now analyzed the consequences of eliminating a substantial part of the cell-cycle inhibitory activity in the cell by generating a mouse model, which combines the absence of both p21 Cip1 and p27 Kip1 proteins with the endogenous expression of a Cdk4 R24C mutant insensitive to Ink4 inhibitors. Pairwise combination of Cdk4 R24C, p21-null and p27-null alleles results in frequent hyperplasias and tumors, mainly in cells of endocrine origin such as pituitary cells and in mesenchymal tissues. Interestingly, complete abrogation of p21 Cip1 and p27 Kip1 in Cdk4 R24C mutant mice results in a different phenotype characterized by perinatal death accompanied by general hypoplasia in most tissues. This phenotype correlates with increased replicative stress in developing tissues such as the nervous system and subsequent apoptotic cell death. Partial inhibition of Cdk4/6 rescues replicative stress signaling as well as p53 induction in the absence of cell-cycle inhibitors. We conclude that one of the major physiological activities of cell-cycle inhibitors is to prevent replicative stress during development.

Highlights in Resistance Mechanism Pathways for Combination Therapy

“…There are two major families of physiological CKI that regulate the cell cycle through cyclin-CDK activity in animals: INK4 and CIP/KIP families. They are both allosteric inhibitors of CDKs [71].…”

Compromising the constitutive p16INK4a expression sensitizes human neuroblastoma cells to Hsp90 inhibition and promotes premature senescence

“…Prolonged cytostasis can trigger senescence response and facilitate progressive elimination of nondividing cells . The increased nucleus to cytoplasmic ratio correlating with increased senescence‐associated‐ β‐ galactosidase (SA β‐ gal) staining (Figure A,B) and γ‐H2AX expression (Figure C) therefore, suggests activation of senescence response in KD cells, however, in response to 17AAG treatment.…”

Evaluation of Terpenes Psiadin, Plectranthone, and Saudinolide as Selective Anti-Cancer Agents against Hepatic Carcinoma Cells

“…There was a small reduction in CDK2 which is thought to drive cells' progression into S and M phase [27]. An interacting factor p-KIP [28] was increased by psiadin. This is known to inhibit the interaction of CDK4/6 with cyclin D which complex is involved in RB phosphorylation.…”