Cell Cycle Control by PTEN

Abstract

Continuous and error-free chromosome inheritance through the cell cycle is essential for genomic stability and tumor suppression. However, accumulation of aberrant genetic materials often causes the cell cycle to go awry, leading to malignant transformation. In response to genotoxic stress, cells employ diverse adaptive mechanisms to halt or exit the cell cycle temporarily or permanently. The intrinsic machinery of cycling, resting, and exiting shapes the cellular response to extrinsic stimuli, whereas prevalent disruption of the cell cycle machinery in tumor cells often confers resistance to anticancer therapy. Phosphatase and tensin homolog (PTEN) is a tumor suppressor and a guardian of the genome that is frequently mutated or deleted in human cancer. Moreover, it is increasingly evident that PTEN deficiency disrupts the fundamental processes of genetic transmission. Cells lacking PTEN exhibit cell cycle deregulation and cell fate reprogramming. Here, we review the role of PTEN in regulating the key processes in and out of cell cycle to optimize genomic integrity.

Keywords: PTEN; cell cycle; genetic transmission; quiescence; senescence.

Figure 1

PTEN induces G1 arrest to prevent uncontrolled proliferation and chromosome instability (CIN). Multiple mechanisms are involved in PTEN-mediated inhibition of the G1-S transition. PTEN can increase the expression of p27^Kip2 or block its proteolytic degradation. Loss of PTEN induces SCFS^Skp2-dependent ubiquitination of p27^Kip2, which results in the reduction of p27^Kip2 and activation of CDK2, leading to acceleration of the G1-S transition (shown with a green background to indicate aberrant cell cycle regulation). While the induction of p27^Kip2 is attributed to the function of cytoplasmic PTEN (shown with a yellow background), PTEN has a nuclear function (pink background) of downregulating cyclin D. In addition to reducing cyclin D, nuclear PTEN can interact with p300 to promote acetylation and stability of p53, resulting in G1 arrest Moreover, PTEN can translocate into the nucleus to elicit a p53-dependent G1 arrest by serving as a target of phosphorylation signaling cascade comprised of PP2A and GSK3B, in response to an increased ROS level following SPRY2 depletion.

Figure 2

PTEN controls the G2-M transition to prevent bypass of the G2 checkpoints and premature entry into mitosis (M). In response to genotoxic stress, PTEN functions to activate the DNA damage checkpoint by suppressing PI3K/AKT-dependent CHK1 phosphorylation and maintaining its nuclear localization and stability. PTEN also promotes TOP2A-mediated DNA decatenation checkpoint by interacting with TOP2A and preventing its degradation. Moreover, PTEN can form a complex with cyclin B1 and CDK1, accumulation of which in the nucleus prevents cell cycle progression from G2 to M. The nuclear translocation of PTEN is mediated by its dephosphorylation following inhibition of Notch signaling. Phosphorylation of PTEN can be induced by the ATR-CHK1-CKII pathway in response to stalled DNA replication forks, or following depletion of CHFR, a checkpoint protein controlling entry to mitosis (shown with green background to indicate aberrant cell cycle regulation). PTEN phosphorylation represents an inactivation state that results in accelerated G2-M transition due to bypass of the DNA damage checkpoint or premature entry into mitosis, leading to genomic instability.