CHOP (GADD153) AND ITS ONCOGENIC VARIANT, TLS-CHOP, HAVE OPPOSING EFFECTS ON THE INDUCTION OF G(1)/S ARREST
CHOP (GADD153) AND ITS ONCOGENIC VARIANT, TLS-CHOP, HAVE OPPOSING EFFECTS ON THE INDUCTION OF G(1)/S ARREST
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DOI：
10.1101/gad.8.4.453
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发表时间：
1994-02-15
影响因子：
10.5
通讯作者：
RON, D
中科院分区：
文献类型：
--
作者：
BARONE, MV;CROZAT, A;RON, D
生长停滞和DNA损伤诱导基因CHOP（GADD 153）编码来自C/EBP家族的小核蛋白，其最初从培养的脂肪细胞中分离。虽然在正常条件下在细胞中是无活性的，但CHOP基因明显地被各种细胞应激诱导，包括营养剥夺和代谢扰动。这些导致CHOP蛋白在细胞核中积累。由于细胞应激通常导致生长停滞，我们研究了CHOP在这一过程中的意义。将CHOP表达质粒显微注射到NIH-3 T3细胞中阻断了细胞在细胞周期中的进展，通过掺入BrdU（S期标记物）的细胞部分的衰减来测量。通过显微注射细菌表达的CHOP蛋白到同步化细胞中，CHOP作用的细胞周期的精确点被绘制出来，这阻止了细胞从G（1）期进入S期。只有在血清刺激后早期引入蛋白质时才观察到CHOP的这种作用，表明CHOP在所谓的G（1）/S检查点或其附近起作用。CHOP与其他C/EBP蛋白质二聚化，CHOP-C/EBP二聚体远离“经典"C/EBP位点，识别独特的”非经典"位点。突变形式的CHOP蛋白，缺乏亮氨酸拉链二聚化结构域或异常结构的碱性区域，可能参与DNA结合，不能诱导生长停滞。迄今为止仅在人脂肪组织肿瘤粘液样脂肪肉瘤中发现的CHOP的肿瘤特异性形式TLS-CHOP不能引起生长停滞，并且还干扰正常CHOP诱导生长停滞的能力。最近研究表明，细胞营养缺乏可显着诱导CHOP。这表明，CHOP可能在诱导生长停滞途径中发挥作用，该途径由代谢线索触发，并且在脂肪组织中特别重要，脂肪组织是一种在其代谢活性中经历显著变化的器官。TLS-CHOP阻断这一通路可能在粘液样脂肪肉瘤的形成中起机制作用。
The growth arrest and DNA damage-inducible gene CHOP (GADD153) encodes a small nuclear protein from the C/EBP family, originally isolated from adipocytes in culture. Although inactive in cells under normal conditions, the CHOP gene is markedly induced by a variety of cellular stresses, including nutrient deprivation and metabolic perturbations. These lead to accumulation of CHOP protein in the nucleus. Because cellular stress normally leads to growth arrest, we examined the implication of CHOP in this process. Microinjection of CHOP expression plasmids into NIH-3T3 cells blocked the cells from progressing through the cell cycle, measured by an attenuation in the fraction of cells incorporating BrdU, an S-phase marker. The precise point in the cell cycle at which CHOP acts was mapped by microinjection of bacterially expressed CHOP protein into synchronized cells-this blocked the cells from progressing from G(1) to S phase. This effect of CHOP was observed only when the protein was introduced early after serum stimulation suggesting that CHOP works at or around the so-called G(1)/S checkpoint. CHOP dimerizes with other C/EBP proteins and the CHOP-C/EBP dimers are directed away from ''classical'' C/EBP sites recognizing instead unique ''nonclassical'' sites. Mutant forms of the CHOP protein that lack the leucine zipper dimerization domain or the unusually structured basic region, potentially involved in DNA binding, fail to induce growth arrest. A tumor-specific form of CHOP, TLS-CHOP, that has been found so far exclusively in the human adipose tissue tumor myxoid liposarcoma, fails to cause growth arrest and furthermore interferes with the ability of normal CHOP to induce growth arrest. CHOP has been shown recently to be markedly inducible by nutritional deprivation of cells. This suggests that CHOP may play a role in an inducible growth arrest pathway that is triggered by metabolic cues and is of particular importance in adipose tissue-an organ that undergoes marked changes in its metabolic activity. Blocking of this pathway by TLS-CHOP may play a mechanistic role in the establishment of myxoid liposarcoma.