Mitotic Kinases and p53 Signaling

Abstract

Mitosis is tightly regulated and any errors in this process often lead to aneuploidy, genomic instability, and tumorigenesis. Deregulation of mitotic kinases is significantly associated with improper cell division and aneuploidy. Because of their importance during mitosis and the relevance to cancer, mitotic kinase signaling has been extensively studied over the past few decades and, as a result, several mitotic kinase inhibitors have been developed. Despite promising preclinical results, targeting mitotic kinases for cancer therapy faces numerous challenges, including safety and patient selection issues. Therefore, there is an urgent need to better understand the molecular mechanisms underlying mitotic kinase signaling and its interactive network. Increasing evidence suggests that tumor suppressor p53 functions at the center of the mitotic kinase signaling network. In response to mitotic spindle damage, multiple mitotic kinases phosphorylate p53 to either activate or deactivate p53-mediated signaling. p53 can also regulate the expression and function of mitotic kinases, suggesting the existence of a network of mutual regulation, which can be positive or negative, between mitotic kinases and p53 signaling. Therefore, deciphering this regulatory network will provide knowledge to overcome current limitations of targeting mitotic kinases and further improve the results of targeted therapy.

Role for polo-like kinase 4 in mediation of cytokinesis

“…The observed spatial-temporal differences in subcellular distribution of phospho-PLK4 have not been reported previously (10, 11, 22). To date, one other group has described PLK4 localization outside of centrosomes (at the central spindle) and provided evidence for a cytokinesis defect in PLK4 −/− cells (14, 15, 31).…”

“…PLK4 functions at the intersection of mitotic and DNA damage pathways (10), and aberrant expression is associated with centriole increases and centrosome dysfunction (11, 12). This may affect control of cell division and play a role in genomic instability.…”

TP53 mutation‐correlated genes predict the risk of tumor relapse and identify MPS1 as a potential therapeutic kinase in TP53‐mutated breast cancers

“…TP53 is capable to regulate a number of checkpoint and mitotic kinases; few of these have been recently investigated as potential targets for therapies (Ha and Breuer, 2012). The MPS1 gene encodes for a dual serine/threonine kinase, which is involved in the mitotic spindle assembly checkpoint (SAC) (Jones et al., 2005; Weiss and Winey, 1996), chromosome stability (Leng et al., 2006), DNA damage checkpoints (Wei et al., 2005) and the TP53‐dependent mitotic checkpoint (Huang et al., 2009c).…”

Prognosis, Biology, and Targeting of TP53 Dysregulation in Multiple Myeloma

“…A tightly regulated feedback loop has been reported between P53 and mitotic kinases (eg, WEE1, PLK1, NEK2, BUB1, TTK, AURKB and PLK1) [79,[82][83][84]. Phosphorylation of P53 in response to mitotic spindle damage has also been reported [85]. The intricate details of the mechanisms and regulatory signals between mitotic kinases and P53 remain poorly understood, but P53 dysfunction disrupts this critical regulation, resulting in abrogation of the G1 checkpoint and upregulation of mitotic kinases allowing cells to override the G2/M checkpoints and contribute to genome instability and tumorigenesis.…”