Claspin activates ATR, a lipid kinase, as a mediator foring molecule in the cellular DNA replication stress response, and activates Chk1 via its CKBD. On the other hand, during the nutrition (serum)-induced cell proliferationinitiation of proliferation from serum starvation, PI3 kinase, another lipid kinase, is activated, and Claspin recruits PDK1 via its CKBD, playing an important role in activating on of the PI3K-mTOR pathway.
Newswise —
Scientists from the Genome Dynamics Project team at the Tokyo Metropolitan Institute of Medical Science have uncovered a novel mechanism that regulates cellular proliferation in response to serum, which is known to trigger the growth of resting cells.
The phosphoinositide 3-kinase (PI3K) - mammalian target of rapamycin (mTOR) pathway is a crucial pathway that regulates cellular growth, particularly during the G1/G0 preparative stages for proliferation. This pathway is responsible for sensing and responding to nutrient availability, and dysregulation of the mTOR signaling pathway is closely associated with various human diseases, including different types of cancers. Additionally, during the S phase of the proliferation cycle, the replication stress checkpoint pathway plays a vital role in safeguarding the genome against potential damages that may arise during DNA replication. Precise regulation of both these pathways is essential to prevent genome instability, which can lead to uncontrolled growth of cancer cells.
Claspin, a critical factor in the replication stress checkpoint signaling, plays a key role in receiving signals from the upstream lipid kinase, ATR, and transmitting them to the downstream kinase, Chk1. This pathway helps prevent cell cycle progression that could threaten the integrity of the genome when replication forks stall. Notably, these nuclear events involving Claspin and Chk1 have not been directly linked to the PI3K-mTOR pathway, which has traditionally been assumed to primarily occur in the cytoplasm. However, there have been reports of the presence of PI3K-mTOR pathway factors in nuclei, indicating that there may be additional complexity and cross-talk between these signaling pathways in different cellular compartments. Further research is needed to fully elucidate the interplay between these pathways in the nucleus and cytoplasm during cellular proliferation and DNA replication stress response.
Living organisms have evolved stress response systems to cope with various types of stress. In the cellular response pathway to replication stress, a signal is transmitted from a sensor kinase (ATR) to an effector kinase (Chk1), leading to a temporary halt in replication and cell division. Claspin serves as a crucial mediator in this signal transduction process, playing an essential role in the checkpoint response to replication stress.
Researchers Chi-Chun Yang, Ph.D., and Hisao Masai, Ph.D., from the Tokyo Metropolitan Institute of Medical Science have made a groundbreaking discovery regarding Claspin's novel function in the nutrition-induced signaling pathway. Their findings reveal that Claspin plays a crucial role in the activation of the PI3K-PDK1-mTOR pathway, as well as its downstream factors, and is essential for cell survival during serum-induced growth restart. This sheds new light on Claspin's involvement in cellular responses to nutrition and serum-induced growth, providing valuable insights into its multifaceted roles in cellular signaling pathways.
Masai expressed his surprise, saying, "This was completely unexpected. The PI3K-mTOR pathway, which is a major nutrient-induced pathway, has been extensively studied, but no functional links to nuclear events or factors have been known. We are excited to discover that Claspin plays unexpected and essential roles in the mTOR pathway. Our studies also suggest a striking similarity between Claspin's role in the activation of the replication checkpoint and its potential mode of action in the nutrition-induced signal transduction, involving the upstream lipid kinase (PI3K) and downstream kinases (PDK1 and mTOR)." This discovery opens up new possibilities for understanding the intricate connections between Claspin, cellular signaling pathways, and nutrient-induced responses, offering valuable insights into the complexity of cellular regulatory mechanisms.
The study would provide new targets for therapeutic interventions of metabolic disorders such as obesity, diabetes, and cancers resulting from the dysregulation of the mTOR pathway.
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