Lee D W, Zhang K, Ning Z Q, Raabe E H, Tintner S, Wieland R, Wilkins B J, Kim J M, Blough R I, Arceci R J
Division of Hematology/Oncology, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Cancer Res. 2000 Jul 1;60(13):3612-22.
To identify genes involved in cell growth and/or apoptosis in leukemia, differential display was used to identify mRNAs that showed altered expression levels after cytokine withdrawal from the cytokine-dependent MO7e cell line. Sequence analysis of one transcript that showed a profound decrease in expression after cytokine withdrawal revealed it to be a member of the SNF2 family of chromatin remodeling ATPases. This cDNA had a 2514-nucleotide (838-amino acid) open reading frame and encoded an additional 230 amino acids at the NH2 terminus compared with the murine homologue, lsh, and the human counterpart, Hells. This gene locus has been designated SMARCA6 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 6). The highest levels of mRNA expression in humans are observed in proliferative tissues such as the thymus, testis, and bone marrow. Whereas cytokine withdrawal in MO7e cells leads to apoptosis and decreased mRNA expression, growth arrest without the induction of apoptosis of MO7e cells also leads to down-regulation of mRNA expression, suggesting an association with cell proliferation and not suppression of apoptosis. Nuclear localization of this SNF2-like putative helicase is dependent on a nuclear localization sequence located in the NH2-terminal region. Based on sequence homology to other SNF2-like helicases, the pattern of tissue expression, and the association of expression with cell proliferation, we refer to the protein product as proliferation-associated SNF2-like gene product [PASG (D. W. Lee et al., Blood, 94: 594a, 1999)]. Examination of acute myelogenous leukemia and acute lymphoblastic leukemia samples revealed a high frequency of a PASG transcript containing an in-frame 75-nucleotide deletion, which codes for a conserved motif known to be critical for the transactivation activity of a related yeast SWI/SNF polypeptide. These results extend our knowledge of this SNF2-like family member and suggest a role for PASG in leukemogenesis.
为了鉴定白血病中参与细胞生长和/或凋亡的基因，采用差异显示技术来鉴定在细胞因子依赖性MO7e细胞系中撤除细胞因子后表达水平发生改变的mRNA。对一种在撤除细胞因子后表达显著下降的转录本进行序列分析，发现它是染色质重塑ATP酶SNF2家族的成员。与小鼠同源物lsh和人类对应物Hells相比，该cDNA有一个2514个核苷酸（838个氨基酸）的开放阅读框，并且在NH2末端额外编码230个氨基酸。该基因位点已被命名为SMARCA6（SWI/SNF2相关、基质相关、肌动蛋白依赖性染色质调节因子，A亚家族，成员6）。在人类中，mRNA表达水平最高的是在增殖组织如胸腺、睾丸和骨髓中。虽然在MO7e细胞中撤除细胞因子会导致凋亡和mRNA表达下降，但MO7e细胞的生长停滞而不诱导凋亡也会导致mRNA表达下调，这表明其与细胞增殖有关，而不是抑制凋亡。这种SNF2样假定解旋酶的核定位依赖于位于NH2末端区域的核定位序列。基于与其他SNF2样解旋酶的序列同源性、组织表达模式以及表达与细胞增殖的关联，我们将该蛋白质产物称为增殖相关SNF2样基因产物[PASG（D.W. Lee等人，《血液》，94：594a，1999）]。对急性髓性白血病和急性淋巴细胞白血病样本的检测发现，含有一个75个核苷酸框内缺失的PASG转录本频率很高，该缺失编码一个已知对相关酵母SWI/SNF多肽的反式激活活性至关重要的保守基序。这些结果扩展了我们对这个SNF2样家族成员的认识，并提示PASG在白血病发生中起作用。
