When a cell senses a signal for growth

Researchers from the Genome Dynamics Project team at the Tokyo Metropolitan Institute of Medical Science· revealed a novel mechanism that controls cell proliferation in response to serum, which triggers resting cell growth.

One of the main pathways for cell growth is the phosphoinositide 3-kinase (PI3K) –mTOR (mechanistic/mammalian target of rapamycin) pathway. mTOR regulates cellular responses to nutrient availability. Dysregulation of the mTOR signaling pathway is intimately involved in many human diseases, especially many different human cancers. This pathway especially plays a major role during G1/G0, the preparatory stage for proliferation. Another key pathway during the proliferation cycle, especially during the S phase, is the replication stress checkpoint pathway. This pathway protects the genome from potential damage that may occur during the DNA replication process. Both pathways need to be regulated precisely to prevent genomic instability which will lead to uncontrolled growth of cancer cells.

Claspin is a key factor that mediates replication voltage checkpoint signaling. It receives signals from the upstream lipid kinase, ATR, and transmits them to the downstream kinase, Chk1. Chk1 prevents genome-threatening cell cycle progression in the face of stalled replication forks. These nuclear events have not been linked to the PI3K-mTOR pathway which is assumed to occur primarily in the cytoplasm, although the presence of the latter factor in the nuclei has been reported.

Living organisms are exposed to various types of stress, and they have developed stress response systems to deal with these situations. In the cellular response pathway to replication stress, a signal is transmitted from the sensor kinase (ATR) to the effector kinase (Chk1) to temporarily halt the progression of cell division and replication. Claspin is a mediator of this signal, which is important for checkpoint signal transduction.

Chi-Chun Yang, Ph.D, and Hisao Masai, Ph.D, at the Tokyo Metropolitan Institute of Medical Science discovered a new function of Claspin in nutrient-induced signaling pathways. The researchers found that Claspin is essential for activation of the PI3K-PDK1-mTOR pathway and downstream factors as well as for cell survival during serum-induced growth resumption.

Masai said, “This is really unexpected. The PI3K-mTOR pathway, the major nutrient-induced pathway, has been studied intensively, but no functional link to nuclear events/factors is known. We are very pleased to know that Claspin plays an important and unexpected role in the mTOR pathway. Our studies also demonstrate a striking similarity of Claspin-mediated activation of replication checkpoints and their mode of action potential in nutrient-induced signal transduction from upstream lipid kinases (PI3K) to downstream kinases (PDK1 and mTOR).

This study will provide new targets for therapeutic interventions for metabolic disorders such as obesity, diabetes, and cancer due to dysregulation of the mTOR pathway.