The intracellular tyrosine kinase Brk sensitizes non-transformed cells to inducers of apoptosis
The intracellular tyrosine kinase Brk sensitizes non-transformed cells to inducers of apoptosis
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DOI：
10.4161/cc.4.9.1965
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发表时间：
2005-09-01
期刊：
影响因子：
4.3
通讯作者：
Tyner, AL
中科院分区：
文献类型：
--
作者：
Haegebarth, A;Nunez, R;Tyner, AL
细胞内酪氨酸激酶Brk在再生上皮组织中表达，在胃肠道和皮肤中表达水平最高。在这些组织中，Brk局限于正在退出细胞周期并进行终末分化的上皮细胞。虽然Brk在乳腺中不表达，但在原发性乳腺肿瘤和乳腺肿瘤细胞系中经常被诱导表达。为了确定Brk的潜在致癌功能，我们利用了对转化高度敏感的永生化Rat1a大鼠成纤维细胞系。我们生成了稳定过表达野生型和激活Brk的Rat1a细胞系，并分析了它们在应激和DNA损伤下的生长特性和凋亡能力。过表达Brk不会诱导不依赖于锚定的生长，也没有观察到细胞形态或细胞周期进程的变化。然而，当组成性表达时，Brk使Rat1a细胞对多种凋亡刺激敏感，包括血清剥夺和紫外线照射和血清饥饿的组合。这些发现表明，Brk不促进非转化细胞的增殖，但在dna损伤和应激的凋亡反应中发挥积极作用。
The intracellular tyrosine kinase Brk is expressed in regenerating epithelial tissues with highest levels in the gastrointestinal tract and skin. In these tissues, Brk is restricted to epithelial cells that are exiting the cell cycle and undergoing terminal differentiation. While not expressed in mammary gland, Brk expression is often induced in primary breast tumors and breast tumor cell lines. To identify potential oncogenic functions of Brk, we utilized the immortalized Rat1a rat fibroblast cell line that is highly sensitive to transformation. We generated Rat1a cell lines that stably overexpress wild-type and activated Brk, and we analyzed their growth properties and ability to undergo apoptosis in response to stress and DNA damage. Overexpression of Brk did not induce anchorage-independent growth, and no changes in cell morphology or cell cycle progression were observed. However, when constitutively expressed, Brk sensitized Rat1a cells to a variety of apoptotic stimuli including serum deprivation and a combination of UV irradiation and serum starvation. These findings indicate that Brk does not promote proliferation of non-transformed cells, but plays a positive role in the regulation of the apoptotic response to DNA-damage and stress.