Abstract
Simple SummaryCancer is increasingly viewed as a cell cycle disease in that the dysregulation of the cell cycle machinery is a common feature in cancer. The Hippo signaling pathway consists of a core kinase cascade as well as extended regulators, which together control organ size and tissue homeostasis. The aberrant expression of cell cycle regulators and/or Hippo pathway components contributes to cancer development, and for this reason, we specifically focus on delineating the roles of the Hippo pathway in the cell cycle. Improving our understanding of the Hippo pathway from a cell cycle perspective could be used as a powerful weapon in the cancer battlefield.Cell cycle progression is an elaborate process that requires stringent control for normal cellular function. Defects in cell cycle control, however, contribute to genomic instability and have become a characteristic phenomenon in cancers. Over the years, advancement in the understanding of disrupted cell cycle regulation in tumors has led to the development of powerful anti-cancer drugs. Therefore, an in-depth exploration of cell cycle dysregulation in cancers could provide therapeutic avenues for cancer treatment. The Hippo pathway is an evolutionarily conserved regulator network that controls organ size, and its dysregulation is implicated in various types of cancers. Although the role of the Hippo pathway in oncogenesis has been widely investigated, its role in cell cycle regulation has not been comprehensively scrutinized. Here, we specifically focus on delineating the involvement of the Hippo pathway in cell cycle regulation. To that end, we first compare the structural as well as functional conservation of the core Hippo pathway in yeasts, flies, and mammals. Then, we detail the multi-faceted aspects in which the core components of the mammalian Hippo pathway and their regulators affect the cell cycle, particularly with regard to the regulation of E2F activity, the G1 tetraploidy checkpoint, DNA synthesis, DNA damage checkpoint, centrosome dynamics, and mitosis. Finally, we briefly discuss how a collective understanding of cell cycle regulation and the Hippo pathway could be weaponized in combating cancer.
Highlights
The cell cycle is divided into four phases: G1 phase, S phase, G2 phase, and M phase [1,2]
The INK4 family inhibits Cyclin D-CDK4/6, while the Cip/Kip families are the pan-CDK inhibitors [16]. Another mechanism for monitoring the order and accuracy of the cell cycle is via cell cycle checkpoints, including the G1 tetraploidy checkpoint mediated by p53 and pRb; the DNA damage checkpoint mediated by ATM, ATR, CHK1, CHK2, BRCA1, BRCA2, PARP1, p53, etc.; and the spindle assembly checkpoint mediated by MPS1, MAD1, MAD2, BUB1, BUBR1, etc. [17–21]
kidney and brain enriched (KIBRA) is phosphorylated by CDK1 at S542 and S931 in mitosis, and the CDK1-mediated phosphorylation of KIBRA is reversed by Cdc14A/B [170]
Summary
The cell cycle is a highly ordered and precise process that ensures the equal distribution of genetic materials to two daughter cells. Cyclin D-CDK4/6 phosphorylates the retinoblastoma protein (pRb), leading to the partial activation of the E2 factor (E2F), a key transcription factor that pushes the cells through the restriction point (R point) by up-regulating genes critical for cell cycle transition The INK4 family inhibits Cyclin D-CDK4/6, while the Cip/Kip families are the pan-CDK inhibitors [16] Another mechanism for monitoring the order and accuracy of the cell cycle is via cell cycle checkpoints, including the G1 tetraploidy checkpoint mediated by p53 and pRb; the DNA damage checkpoint mediated by ATM, ATR, CHK1, CHK2, BRCA1, BRCA2, PARP1, p53, etc.; and the spindle assembly checkpoint mediated by MPS1, MAD1, MAD2, BUB1, BUBR1, etc. P16INK4a, p15INK4b, p27KIP1, p57KIP2, and pRb are deleted, mutated, epigenetically repressed, or degraded [22] The checkpoint proteins such as p53, ATM, CHK2, ATR, BRCA1, BRCA2, BUB1, and BUBR1 are inactivated, whereas PARP1 is overexpressed in tumors [24–26]. Cell cycle dysregulation is a doubleedged sword, which on one hand leads to an aggressive cancer phenotype, yet on the other hand provides targets for anti-cancer therapies
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