CDK2 Phosphorylation of Smad2 Disrupts TGF-β Transcriptional Regulation in Resistant Primary Bone Marrow Myeloma Cells
CDK2 Phosphorylation of Smad2 Disrupts TGF-β Transcriptional Regulation in Resistant Primary Bone Marrow Myeloma Cells
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DOI：
10.4049/jimmunol.0713726
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发表时间：
2009-02-15
影响因子：
4.4
通讯作者：
Chen-Kiang, Selina
中科院分区：
文献类型：
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作者：
Baughn, Linda B.;Di Liberto, Maurizio;Chen-Kiang, Selina
TGF-β1对生长抑制的耐药性在癌症中很常见。但是，在造血恶性肿瘤中，这种途径中的突变很少见。在多发性骨髓瘤（血浆细胞的致命癌症）中，由于细胞周期和凋亡对照损失，恶性细胞在TGF-β富含TGF-β的骨髓中积累。本文我们表明，TGF-beta激活SMAD2，但由于无法激活G，Cyclin依赖性激酶（CDK）抑制剂（P15（INK4B），，P15（INK4B），，由于其无法激活G激活G。 P21（CIP1/WAF1），P27（KIP1），P57（KIP2））或压抑C-MYC和BCL-2转录。与CDK的异常激活相关，Smad2在THR（8）（PT8）上的CDK依赖性磷酸化（PT8）是一种与SMAD活性受损相关的修饰，即使在无症状的单克隆单克隆γ型骨髓瘤细胞中也升高。此外，CDK2是骨髓瘤细胞中T8磷酸化的主要CDK，导致抑制SMAD2-SMAD4关联，从而无法通过SMAD2进行转录调节。我们的发现提供了第一个直接证据，表明PT8 SMAD2伴侣在原代癌细胞中CDK2对TGF-β耐药性的失调，它们表明CDK2磷酸化对SMAD2功能的破坏是多发性骨髓瘤中TGF-β耐药性的一种机制。 《免疫学杂志》，2009，182：1810-1817。
Resistance to growth suppression by TGF-beta 1 is common in cancer; however, mutations in this pathway are rare in hematopoietic malignancies. In multiple myeloma, a fatal cancer of plasma cells, malignant cells accumulate in the TGF-beta-rich bone marrow due to loss of both cell cycle and apoptotic controls. Herein we show that TGF-beta activates Smad2 but fails to induce cell cycle arrest or apoptosis in primary bone marrow myeloma and human myeloma cell lines due to its inability to activate G, cyclin-dependent kinase (CDK) inhibitors (p15(INK4b), p21(CIP1/WAF1), p27(KIP1), p57(KIP2)) or to repress c-myc and Bcl-2 transcription. Correlating with aberrant activation of CDKs, CDK-dependent phosphorylation of Smad2 on Thr(8) (pT8), a modification linked to impaired Smad activity, is elevated in primary bone marrow myeloma cells, even in asymptomatic monoclonal gammopathy of undetermined significance. Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2. Our findings provide the first direct evidence that pT8 Smad2 couples dysregulation of CDK2 to TGF-beta resistance in primary cancer cells, and they suggest that disruption of Smad2 function by CDK2 phosphorylation acts as a mechanism for TGF-beta resistance in multiple myeloma. The Journal of Immunology, 2009, 182: 1810-1817.