Chen Ji-Long, Limnander Andre, Rothman Paul B
Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Blood. 2008 Feb 1;111(3):1677-85. doi: 10.1182/blood-2007-04-083808. Epub 2007 Nov 27.
The precise mechanisms by which Abl oncogenes transform hematopoietic cells are unknown. We have examined the role of Pim kinases in v-Abl-mediated transformation. In v-Abl transformants, expression of Pim-1 and Pim-2, but not Pim-3, is dependent on Abl kinase activity. Transformation assays demonstrate that v-Abl cannot efficiently transform bone marrow cells derived from Pim-1(-/-)/Pim-2(-/-) mice. Ectopic expression of either Pim-1 or Pim-2 in Pim-1(-/-)/Pim-2(-/-) cells restores transformation by v-Abl, strongly suggesting that either Pim-1 or Pim-2 is required for v-Abl-mediated tumorigenesis. Interestingly, the combined deficiency of Pim-1, Pim-2, and Suppressor of Cytokine Signalling (SOCS)-1 resulted in partial restoration of v-Abl transformation efficiency. In addition, Pim kinases are involved in modification of SOCS-1 and in regulating SOCS-1 protein levels in v-Abl-transformed cells. Furthermore, Pim kinases regulate the proapoptotic proteins Bcl-XS and BAD. Pim kinases inhibit the expression of Bcl-XS. Pim deficiency decreases the phosphorylation levels of BAD, whereas ectopic expression of Pim-1 increases the amount of phospho-BAD. This correlates with an increased protection from apoptosis in Abl transformants expressing Pim kinases. Together, these data suggest that Pim kinases play a key role in the v-Abl transformation, possibly via participating in modulation of SOCS-1 and via regulating the apoptotic signaling.
Abl癌基因转化造血细胞的确切机制尚不清楚。我们研究了Pim激酶在v-Abl介导的转化中的作用。在v-Abl转化体中，Pim-1和Pim-2而非Pim-3的表达依赖于Abl激酶活性。转化试验表明，v-Abl不能有效地转化源自Pim-1(-/-)/Pim-2(-/-)小鼠的骨髓细胞。在Pim-1(-/-)/Pim-2(-/-)细胞中异位表达Pim-1或Pim-2可恢复v-Abl介导的转化，强烈提示Pim-1或Pim-2是v-Abl介导的肿瘤发生所必需的。有趣的是，Pim-1、Pim-2和细胞因子信号转导抑制因子（SOCS）-1的联合缺陷导致v-Abl转化效率部分恢复。此外，Pim激酶参与SOCS-1的修饰并调节v-Abl转化细胞中SOCS-1的蛋白水平。此外，Pim激酶调节促凋亡蛋白Bcl-XS和BAD。Pim激酶抑制Bcl-XS的表达。Pim缺陷降低BAD的磷酸化水平，而Pim-1的异位表达增加磷酸化BAD的量。这与表达Pim激酶的Abl转化体中对凋亡的保护增加相关。总之，这些数据表明Pim激酶在v-Abl转化中起关键作用，可能是通过参与SOCS-1的调节和调节凋亡信号转导来实现的。
