p34^SEI-1 inhibits doxorubicin-induced senescence through a pathway mediated by protein kinase C-δ and c-Jun-NH₂-kinase 1 activation in human breast cancer MCF7 cells

In this study, we describe a novel function of the p34^SEI-1 protein, which is both an oncogenic protein and a positive regulator of the cell cycle. The p34^SEI-1 protein was found to inhibit doxorubicin-induced senescence. We investigated the molecular mechanisms of the inhibitory effect of p34^SEI-1 on senescence. First, we found that the activation of protein kinase C-δ (PKC-δ), which is cleaved into a 38 kDa active form from a 78 kDa pro-form, induced after doxorubicin treatment, was inhibited by p34^SEI-1. Furthermore, p34^SEI-1 induced the ubiquitination of PKC-δ. Yet, there is no interaction between p34 ^SEI-1 and PKC-δ. We also found that the phosphorylation of c-Jun-NH₂-kinase 1 (JNK1) induced after doxorubicin treatment was suppressed by p34^SEI-1, but not in JNK2. Consistently, pharmacologic or genetic inactivation of either PKC-δ or JNK1 was found to inhibit doxorubicin-induced senescence. In addition, the genetic inactivation of PKC-δ by PKC-δ small interfering RNA resulted in an inhibition of JNK1 activation, but PKC-δ expression was not inactivated by JNK1 small interfering RNA, implying that the activation of JNK1 could be dependently induced by PKC-δ. Therefore, p34^SEI-1 inhibits senescence by inducing PKC-δ ubiquitination and preventing PKC-δ-dependent phosphorylation of JNK1.