1. Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK

Correspondence to: Tim Hunt¹ Correspondence and requests for materials should be addressed to T.H. (Email: tim.hunt@cancer.org.uk).

Abstract

Fertilization induces a transient increase in cytoplasmic Ca²⁺ concentration in animal eggs that releases them from cell cycle arrest in the second meiotic metaphase¹. In frog eggs, Ca²⁺ activates Ca²⁺/calmodulin-activated kinase, which inactivates cytostatic factor^{2, 3, 4, 5}, allowing the anaphase-promoting factor to turn on and ubiquitinate cyclins and securin, which returns the cell cycle to interphase⁶. Here we show that the calcium-activated protein phosphatase calcineurin⁷ is also important in this process. Calcineurin is transiently activated after adding Ca²⁺ to egg extracts, and inhibitors of calcineurin such as cyclosporin A (ref. 8) delay the destruction of cyclins, the global dephosphorylation of M-phase-specific phosphoproteins and the re-formation of a fully functional nuclear envelope. We found that a second wave of phosphatase activity directed at mitotic phosphoproteins appears after the spike of calcineurin activity. This activity disappeared the next time the extract entered M phase and reappeared at the end of mitosis. We surmise that inhibition of this second phosphatase activity is important in allowing cells to enter mitosis, and, conversely, that its activation is required for a timely return to interphase. Calcineurin is required to break the deep cell cycle arrest imposed by the Mos-MAP (mitogen-activated protein) kinase pathway^{4, 5, 9}, and we show that Fizzy/Cdc20, a key regulator of the anaphase-promoting factor⁶, is an excellent substrate for this phosphatase.

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