Schulze-Luehrmann Jan, Santner-Nanan Brigitte, Jha Mithilesh Kumar, Schimpl Anneliese, Avots Andris, Serfling Edgar
Department of Molecular Pathology, Institute of Pathology, D-97080 Wuerzburg, Germany.
Blood. 2002 Aug 1;100(3):954-60. doi: 10.1182/blood-2002-01-0089.
Hematopoietic progenitor kinase 1 (HPK1) is a member of germinal center kinases that is predominantly expressed in hematopoietic cells and transiently activated by T-cell receptor (TCR) triggering. We show here that HPK1 supports apoptosis of T cells. When HPK1 was overexpressed in murine CD4(+) T cells, a substantial increase was observed in spontaneous and TCR/CD3-mediated apoptosis as well as in Fas ligand (FasL) expression. In H2O2-treated EL-4 thymoma cells, which show an increase in reactive oxygen species (ROS) and apoptosis, overexpression of HPK1 enhanced ROS-mediated apoptosis, whereas expression of HPK1 antisense (AS) RNA impaired apoptosis. HPK1 expression also led to a sustained increase in c-Jun N-terminal kinase (JNK) activity, suggesting that JNK activation contributes to the HPK1-mediated apoptosis in H2O2-treated EL-4 cells. Under the same conditions, a rapid cleavage of HPK1 was observed, and overexpression of N- and C-terminal cleavage products in CD4(+) T cells resulted in, similar to full-length HPK1, an increase in apoptosis. In agreement with published data, we show that the C-terminal portion of HPK1 suppresses IkappaBalpha degradation, thereby inhibiting nuclear factor (NF)-kappaB activation. These findings suggest that by inhibiting the antiapoptotic action of NF-kappaB and inducing the proapoptotic activity of JNK, OHPK1 supports apoptosis in T cells.
造血祖细胞激酶1（HPK1）是生发中心激酶家族的成员，主要在造血细胞中表达，并通过T细胞受体（TCR）触发而短暂激活。我们在此表明，HPK1支持T细胞凋亡。当在小鼠CD4(+) T细胞中过表达HPK1时，观察到自发和TCR/CD3介导的凋亡以及Fas配体（FasL）表达有显著增加。在经H2O2处理的EL-4胸腺瘤细胞中，活性氧（ROS）和凋亡增加，HPK1的过表达增强了ROS介导的凋亡，而HPK1反义（AS）RNA的表达则损害了凋亡。HPK1的表达还导致c-Jun氨基末端激酶（JNK）活性持续增加，表明JNK激活有助于H2O2处理的EL-4细胞中HPK1介导的凋亡。在相同条件下，观察到HPK1的快速切割，并且在CD4(+) T细胞中过表达N端和C端切割产物导致与全长HPK1相似的凋亡增加。与已发表的数据一致，我们表明HPK1的C端部分抑制IkappaBalpha降解，从而抑制核因子（NF）-kappaB激活。这些发现表明，通过抑制NF-kappaB的抗凋亡作用并诱导JNK的促凋亡活性，HPK1支持T细胞凋亡。
