EXPRESSION/REGULATION OF PHOSPHODIESTERASE 3 ISOFORMS

环核苷酸磷酸二酯酶（PDEs）通过催化cAMP和cGMP的水解，是环核苷酸介导的细胞内浓度和生物反应（包括免疫/炎症反应）的关键调节剂。了解PDE亚型的细胞调控[属于10个基因家族（PDE1-10）]对于靶向特异性PDE治疗肺部疾病将越来越重要。尽管单个细胞通常包含几个PDE基因家族的代表，但对单个细胞中不同PDE的细胞因子和生长因子调控所涉及的信号通路知之甚少。在小鼠FDCP2早髓样细胞中，IL-4和IGF-1激活PDE3和PDE4，而IL-3仅激活PDE4。对TNFalpha和JAK、PI3-K、PKC和MAPK激酶抑制剂的研究表明，IGF-1和IL-3都通过PI3-K依赖性信号激活PDE3和PDE4。PI3-K下游，调控通路分化；PDE4，而不是PDE3，由MEK/ mapk依赖性信号激活。因此，FDCP2细胞被永久转染野生型（wt）、组成型活性（CA）或激酶失活（KI）形式的MEK和PKB。对这些转染细胞的研究表明，PDE4被MEK/ mapk依赖的信号激活，PDE3被pkb依赖的信号磷酸化和激活。重组小鼠(M) PDE3B在体外被PKB磷酸化和激活；缺乏一致PKB磷酸化位点的截断的MPDE3B突变体未被磷酸化/激活。在表达WT PKB的细胞中，促凋亡蛋白BAD响应IGF-1被磷酸化；磷酸化被8-Br-cAMP或PDE3抑制剂西洛胺阻断。这些和其他数据表明，PDE3B是PKB的下游靶点，如果不是底物，并且可能作为PKB的效应物调节cAMP池，至少部分调节PKB对FDCP2细胞存活/增殖的影响。- PDE3, PDE4，环核苷酸水解，胰岛素，IGF-1，蛋白激酶B， FDCP2造血细胞，细胞存活/增殖

By catalyzing hydrolysis of cAMP and cGMP, cyclic nucleotide phosphodiesterases (PDEs) are critical regulators of intracellular concentrations of, and biological responses mediated by, cyclic nucleotides, including immune/inflammatory responses. Understanding cellular regulation of PDE isoforms [which belong to ten gene families (PDE1-10)] will be of increasing importance for targeting specific PDEs in treating pulmonary disorders. Although individual cells usually contain representatives of several PDE gene families, little is known of signalling pathways involved in cytokine and growth factor regulation of different PDEs in a single cell. In murine FDCP2 promyeloid cells, IL-4 and IGF-1 activate PDE3 and PDE4, whereas IL-3 activates only PDE4. Studies with TNFalpha and inhibitors of JAK, PI3- K, PKC, and MAPK kinases indicate that both IGF-1 and IL-3 activate PDE3 and PDE4 via PI3-K-dependent signals. Downstream of PI3-K, regulatory pathways diverge; PDE4, but not PDE3, is activated by MEK/MAPK-dependent signals. FDCP2 cells were, therefore, permanently transfected with wild type (wt), constitutively active (CA), or kinase inactive (KI) forms of MEK and PKB. Studies with these transfected cells indicated that PDE4 was activated by MEK/MAPK-dependent signals, and that PDE3 was phosphorylated and activated by PKB-dependent signals. Recombinant mouse (M) PDE3B was phosphorylated and activated in vitro by PKB; a truncated MPDE3B mutant lacking consensus PKB phosphorylation sites was not phosphorylated/activated. In cells expressing WT PKB, the proapoptotic protein BAD was phosphorylated in response to IGF-1; phosphorylation was blocked by 8-Br-cAMP or the PDE3 inhibitor cilostamide. These and other data suggest that PDE3B is a downstream target, if not substrate, of PKB and may function as an effector of PKB in regulation of cAMP pools that modulate, at least in part, effects of PKB on survival/proliferation of FDCP2 cells. - PDE3, PDE4, cyclic nucleotide hydrolysis, insulin, IGF-1, Protein Kinase B, FDCP2 hematopoietic cells, cell survival/proliferation