Cytokines control the number of lymphocytes in the body. Too many cytokines can lead to lymphoma; an absence to immunodeficiency. And while it is broadly known that cytokines, like IL-3 and IL-7, block apoptosis, it is less well-recognized that they promote cell proliferation. On page 755, Khaled et al. show that cytokines promote cycling by inhibiting the effects of the stress protein p38 MAP kinase and activating Cdc25A.
Withdrawal of IL-3 or IL-7 from either primary lymphocytes or cytokine-dependent cell lines induces apoptosis in 24 to 36 hours. However, cell cycle arrest starts within the first 8 hours.
The team found that the phosphatase Cdc25A, which must dephosphorylate CDK2 to allow passage through the G1-S boundary, was at the root of the problem. Removal of the cytokines led to activation of p38 MAP kinase, which phosphorylated and targeted Cdc25A for degradation. Without Cdc25A, CDK2 was not activated. Inhibition of p38 or expression of a constitutively active Cdc25A transgene restored cell cycling, even in the absence of cytokines.
The close link between cytokines and cell cycle proteins is remarkable, but perhaps more intriguing is the observation that maintaining the proliferation signals delays cell death. The survival signal is still impaired by the withdrawal of cytokines, but somehow the cycling cells can still escape death for ∼3 days.