Calcium signaling in cell division

Calcium plays a crucial role in regulating the events of cellular division. Calcium acts both to modulate intracellular signaling as a secondary messenger and to facilitate structural changes as cells progress through division. Exquisite control of intracellular calcium dynamics are required, as calcium appears to play a role at multiple cell cycle checkpoints.

The major downstream calcium effectors are the calcium-binding calmodulin protein and downstream calmodulin-dependent protein kinases I / II. Evidence points to this signaling cascade as a major mediator of calcium signaling in cell division.

Meiosis

Historically, one of the most well characterized roles of intracellular calcium is activation of the ovum after sperm fertilization. In deuterosome eggs (mammals, fish, amphibians, ascidians, sea urchins, etc.), successful sperm entry leads to a distinct rise in intracellular calcium ions (Ca²⁺), with mammals and ascidians displaying a series of intracellular calcium spikes required for completion of meiosis....^[1] Unfertilized vertebrate eggs arrest development after meiosis I. This developmental pause is attributed to the vaguely defined cytostatic factor (CSF). Current researches suggest “CSF” is actually multiple pathways working together to halt division at metaphase of meiosis II.^[2] Upon sperm entry into the egg, Ca²⁺ is released from intracellular stores, leading to inhibition of the CSF-arrest mechanism. Calmodulin dependent kinase II was shown to be the protein responsible for converting the Ca²⁺ influx signal into inhibition of CSF and activation of cyclin degradation machinery to degrade cyclin B, resulting in progression through meiosis II.

In mammals, this rise in Ca²⁺ was shown to be driven by IP3 stimulation induced by PLCζ provided by the sperm.^[3] In general, PLC enzymes stimulate calcium release by internal stores through the breakdown of PIP₂ into IP₃ and DAG.

Mitosis

Signaling

Beyond the events of meiosis, changes in Ca²⁺ levels are observed in a variety of organisms at different stages of division, such as nuclear membrane breakdown^[4] and the metaphase-anaphase transition.^[5] Further, recent work has shown mechanically induced rapid entry into mitosis of cells paused in G2.^[6] Further, progression through division requires the presence of calcium (G1/S, G2/M, and metaphase/anaphase), suggesting checkpoints require a calcium-dependent signaling mechanism^[7]

G1/S

Entry into S-phase is calcium dependent. Depleting internal calcium stores inhibits initiation of DNA synthesis. One possible mechanism is that cyclin A synthesis is inhibited, preventing cdk2 activity which is required for initiation of DNA synthesis.^[7]

G2/M

Cell cycle progression is regulated by multiple pathways. It was shown using human cancer cell lines, that the G2/M checkpoint is regulated by CaMKII and MAPK crosstalk. Here, CaMKII activates MEK/ERK, which degrades the cell cycle arresting p27 protein^{[8][better source needed]}

Disease

In general, transformed cells proliferate in a calcium-independent manner, whereas non-transformed cells show high sensitivity to extra-cellular calcium concentration, suggesting oncogenic growth may include disruption of calcium signaling.^[7]

Chromatin Structure

Condensation of chromatin is a vital step in cell division, allowing cells to equally distribute chromosomes to the daughter cells. Recent work has suggested that Ca²⁺ is required for enabling chromatin condensation in prometaphase. Calcium was found to concentrate on condensed DNA to much higher levels compared to normal cytosolic calcium concentration. The role of calcium in condensation was independent of CAMK function, suggesting a purely structural role of Ca²⁺ in chromatin compaction. Further, this result was demonstrated in vitro with extracted chromatin, emphasizing that the mere presence of Ca²⁺ can influence the structure of chromatin^[9]

References

1. McDougall, Alex; Sardet, Christian (1995-03-01). "Function and characteristics of repetitive calcium waves associated with meiosis". Current Biology. 5 (3): 318–328. doi:10.1016/S0960-9822(95)00062-5. ISSN 0960-9822. PMID 7780742.
2. Madgwick, Suzanne; Jones, Keith T. (2007-01-26). "How eggs arrest at metaphase II: MPF stabilisation plus APC/C inhibition equals Cytostatic Factor". Cell Division. 2: 4. doi:10.1186/1747-1028-2-4. ISSN 1747-1028. PMC 1794241. PMID 17257429.
3. Saunders, Christopher M.; Larman, Mark G.; Parrington, John; Cox, Llewellyn J.; Royse, Jillian; Blayney, Lynda M.; Swann, Karl; Lai, F. Anthony (2002-08-01). "PLCζ: a sperm-specific trigger of Ca2+ oscillations in eggs and embryo development". Development. 129 (15): 3533–3544. doi:10.1242/dev.129.15.3533. ISSN 0950-1991. PMID 12117804.
4. Poenie, Martin; Alderton, Janet; Tsien, Roger Y.; Steinhardt, Richard A. (May 1985). "Changes of free calcium levels with stages of the cell division cycle". Nature. 315 (6015): 147–149. doi:10.1038/315147a0. ISSN 1476-4687. PMID 3838803. S2CID 4287089.
5. Poenie, M.; Alderton, J.; Steinhardt, R.; Tsien, R. (1986-08-22). "Calcium rises abruptly and briefly throughout the cell at the onset of anaphase". Science. 233 (4766): 886–889. doi:10.1126/science.3755550. ISSN 0036-8075. PMID 3755550.
6. Gudipaty, S. A.; Lindblom, J.; Loftus, P. D.; Redd, M. J.; Edes, K.; Davey, C. F.; Krishnegowda, V.; Rosenblatt, J. (March 2017). "Mechanical stretch triggers rapid epithelial cell division through Piezo1". Nature. 543 (7643): 118–121. doi:10.1038/nature21407. ISSN 1476-4687. PMC 5334365. PMID 28199303.
7. Takuwa, Noriko; Zhou, Wei; Takuwa, Yoh (1995-02-01). "Calcium, calmodulin and cell cycle progression". Cellular Signalling. 7 (2): 93–104. doi:10.1016/0898-6568(94)00074-L. ISSN 0898-6568. PMID 7794690.
8. Li, Nan; Wang, Chunmei; Wu, Yanan; Liu, Xingguang; Cao, Xuetao (2009-01-30). "Ca2+/Calmodulin-dependent Protein Kinase II Promotes Cell Cycle Progression by Directly Activating MEK1 and Subsequently Modulating p27 Phosphorylation". Journal of Biological Chemistry. 284 (5): 3021–3027. doi:10.1074/jbc.M805483200. ISSN 0021-9258. PMID 19056740. (Retracted, see doi:10.1016/j.jbc.2021.100766)
9. Phengchat, Rinyaporn; Takata, Hideaki; Morii, Kenichi; Inada, Noriko; Murakoshi, Hideji; Uchiyama, Susumu; Fukui, Kiichi (2016-12-02). "Calcium ions function as a booster of chromosome condensation". Scientific Reports. 6 (1): 38281. doi:10.1038/srep38281. ISSN 2045-2322. PMC 5133622. PMID 27910894.