Fez1/Lzts1 a new mitotic regulator implicated in cancer development

Abstract

Considerable evidence has accumulated suggesting that cancer has genetic origin, based on the development of genomic alterations, such as deletions, mutations, and/or methylations in critical genes for homeostasis of cellular functions, including cell survival, DNA replication and cell cycle control. Mechanism controlling the precise timing and sequence of cell cycle events as well as checkpoints insuring fidelity of those events are key targets that when disrupted could result in tumorigenesis. Mitosis is the process by which a cell duplicates its genetic information (DNA), in order to generate two, identical, daughter cells. In addition each daughter cell must receive one centrosome and the appropriate complements of cytoplasm and organelles. This process is conventionally divided in to five distinct stages: prophase, prometaphase, metaphase, anaphase and telophase that correspond to a different morphology of the cell. The entry into mitosis (M) is under the control of the cyclin dependent kinase Cdk1. During G2, the kinases Wee1 and Myt1 phosphorylate Cdk1 at T14/Y15 residues, rendering it inactive. The transition from G2 to M is promoted by the activation of Cdk1 via dephosphorylation by the Cdk1 phosphatase Cdc25C. Activated Cdk1 complexes translocate into the nucleus during prophase where phosphorylate numerous substrates in order to enhance their activation as the cells progresses trough prophase, prometaphase, and metaphase.Recently we identified a new player: FEZ1/LZTS1 that contributes to the fine-tuning of the molecular events that determine progression through mitosis, and here will review its role in cancer development and in M phase regulation.

Figure 1

Structural Functional Domains of Lzts1 protein. Putative phosphorylation motifs of various kinases cAMP-dependent protein kinase A (PKA, in blue), protein kinase C (PKC, in green), cGMP-dependent kinase (PKG, in prugna), casein kinases I and II (CK1 and CK2, in green and in red, respectively), CDC2 kinase (CDC2, in orange), tyrosine kinase (TyrKin, in magenta). The Leucine residues of Leucine zipper motifs are indicated by the gray color.

Figure 2

Progression through the different stages of mitosis in Lzts1^+/+ and Lzts1^-/- cells. During prophase the interaction between Lzts1 and Cdc25C allows high levels of Cdc25C expression and activity resulting in normal progression from prophase to metaphase. In Lzts1 deficient cell during prophase, Cdc25C is rapidly ubiquitinated and degraded thus determining a low activity of the cyclin B1/Cdk1 complex. As a consequence the cell progress faster through prophase and prometaphase and frequently undergo to chromosomes missegregation. Yellow arrows indicate lagging chromosomes in Lzts1^-/- cells.