Cytoskeleton最新文献

Centrosomes catalyze the assembly of a microtubule-based bipolar spindle, essential for the precise chromosome segregation during cell division. At the center of this process lies Polo-Like Kinase 4 (PLK4), the master regulator that controls the duplication of the centriolar core to ensure the correct balance of two centrosomes per dividing cell. Disruptions in centrosome number or function can lead to genetic disorders such as primary microcephaly or drive tumorigenesis via centrosome amplification. In this context, several chemical inhibitors of PLK4 have emerged as promising therapeutic candidates. The inhibition of PLK4 results in the emergence of acentrosomal cells, which undergo prolonged and error-prone mitosis. This aberrant mitotic duration triggers a “mitotic stopwatch” mechanism that activates the tumor suppressor p53, halting cellular proliferation. However, in a multitude of cancers, the efficacy of this mitotic surveillance mechanism is compromised by mutations that incapacitate p53. Recent investigations have unveiled p53-independent vulnerabilities in cancers characterized by chromosomal gain or amplification of 17q23, which encodes for the ubiquitin ligase TRIM37, in response to PLK4 inhibition, particularly in neuroblastoma and breast cancer. This review encapsulates the latest advancements in our understanding of centriole duplication and acentrosomal cell division in the context of TRIM37 amplification, positioning PLK4 as a compelling target for innovative cancer therapeutics.

Centriolar satellites are membrane-less granules that are now accepted as core structural and functional components of the centrosomes and the cilia. While initially associated with centrosome assembly and primary cilia formation, these complexes and their dynamic structures seem to be involved in various other cellular processes, including protein homeostasis, autophagy, and responses to cellular stress. Since the identification of the first centriolar satellite protein, PCM1, substantial progress has been made in understanding the molecular composition and biological functions of centriolar satellites. Here, we review the function of a centriolar satellite protein CEP72, which is emerging as a key component of many essential processes associated with centrosomes and cilia. We describe the complexes it associates with, their function, and the genetic mutations that implicate CEP72 in a range of human disorders.

Cells have an intrinsic ability to rapidly respond to environmental change to regulate cell cycle progression and membrane organisation, thereby affecting cell growth and division. The actin cytoskeleton is a highly dynamic complex of proteins that can rapidly reorganise to change the growth pattern of a cell. Class I myosins are monomeric actin-associated motor proteins that play key roles in diverse cellular functions such as tension sensing and membrane reorganisation, as well as promoting actin polymer nucleation at sites of cell growth. We have analysed the localisation and function of both C. elegans class 1 myosins, HUM-1 (Myo1e) and HUM-5 (Myo1d). Both motors are non-essential. While HUM-1 is expressed in diverse cells and tissues, HUM-5 localises exclusively to a subset of cells in the nervous system. While animals lacking hum-1 displayed a reduced maximal brood size and a delay in embryo release, deleting both hum-1 and hum-5 together shortened C. elegans lifespan. Moreover, we identified that phosphorylation of a conserved serine residue within the Myo1e TH1 domain had an impact on the localisation and function of the motor protein in both C. elegans and the fission yeast, S. pombe, indicating this modification modulates the ability of Myo1e/HUM-1 to interact with phospholipids at the plasma membrane. We conclude that TH1 domain phosphorylation plays a key role in regulating the cellular distribution and function of Myo1e motors across all eukaryotes.

ON THE INNER FRONT COVER: Spermatocytes of Drosophila melanogaster during anaphase of the first meiosis stained for tubulin (green), the kinesin-like Pavarotti (red) and DNA (blue).

Credit: Maria Giovanna Riparbelli and Giuliano Callaini (University of Siena, Siena, Italy)

ON THE FRONT COVER: Spermatocytes of Drosophila melanogaster during metaphase and anaphase of the first meiosis stained for tubulin (green), the kinesin-like Pavarotti (red) and DNA (blue).

Credit: Maria Giovanna Riparbelli and Giuliano Callaini (University of Siena, Siena, Italy)

ON THE BACK COVER: Disruption of the actin cytoskeleton by latrunculin B promotes the translocation of Core-binding factor subunit beta (red) to the cytoplasm of human skeletal muscle. F-actin (green) and DNA (blue) are also shown.

Credit: Yaxin Li and Fumihiko Nakamura (Tianjin University, School of Pharmaceutical Science and Technology, China)

ON THE INNER BACK COVER: GMPCPP stabilized microtubules assembled from 1 μM mung tubulin incubated at 37°C for 114 hours.

Credit: Jashaswi Basu and Chaitanya Athale (Indian Institute of Science Education and Research Pune, India)