MOLECULAR STUDIES ON HTLV X GENE PRODUCT/LTR INTERACTION

HTLV X 基因产物/LTR 相互作用的分子研究

• 批准号: 3079622
• 负责人: William Wachsman
• 金额: $ 7.53万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-01-22 至 1989-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3079622
• 关键词: B lymphocyte; T lymphocyte; complementary DNA; gene deletion mutation; gene expression; gene redundancy; genetic manipulation; genetic transcription; human T cell lymphotropic virus type 1; human T cell lymphotropic virus type 2; human tissue; messenger RNA; molecular cloning; nucleic acid sequence; viral leukemogenesis; virus genetics

The human T-cell leukemia viruses (HTLV) types I and II are lymphotropic type C retroviruses causally associated with certain human T-cell malignancies. These unique viruses, which do not contain sequences related to known oncogenes, cause acute transformation of human T lymphocytes in vitro. The mechanism of HTLV-I induced leukemogenesis is unknown. The HTLV-I and HTLV-II proviruses have been molecularly cloned. Analyses of nucleic acid sequences in HTLV identified, in addition to the typical structural genes, a region, termed X, located between env and the 3' long terminal repeat (LTR). The HTLV-I and HTLV-II X regions are approximately 1.6 kbp in size and conserve 75% of the distal two-thirds of their sequences. These high homology X sequences are also conserved in HTLV-II deletion mutants that are found in cells with more malignant growth characteristics. Recent data indicates that virtually identical HTLV-I and HTLV-II high homology X sequences are expressed as subgenomic RNA, which encode proteins weighing 40 and 37 kD, respectively. Other studies have suggested that the HTLV LTR, a control element for viral expression, is regulated in-trans by a HTLV-related factor. It is likely that the X-encoded protein is a trans-acting regulator of the HTLV LTR and that this gene product serves an analagous function in the process of leukemic transformation of normal T-cells by regulation of genetic control elements in-trans. The overall goal of this proposal is to determine whether the HTLV X gene product influences the behavior of the HTLV LTR. The specific aims are: (1) To clone and express both the HTLV-I and HTLV-II X genes; (2) To determine if the X gene product acts in-trans on the HTLV LTR; (3) To compare the effect of the HTLV-I and HTLV-II X gene product on the LTR; (4) To compare the response of the HTLV-I, HTLV-II, and HTLV-II deletion mutant LTRs to the X gene product; (5) To ascertain if X gene product-LTR interaction is modulated by cellular environment in a variety of lymphoid and non-lymphoid cell lines. These studies will further our understanding of HTLV biology and add to fundamental knowledge regarding the mechanism of viral-induced leukemogenesis. Presently, my focus is in the area of hematologic malignancies and the biology of HTLV. The environment at UCLA, where there is an ongoing program focused on the molecular biology of HTLV, is ideal for continuing my development as an academic hematologist-oncologist.

人类T细胞白血病病毒（HTLV）类型I和II是淋巴机 C型逆转录病毒与某些人类T细胞有因果关系 恶性肿瘤。 这些独特的病毒，不包含与序列相关的序列 对于已知的癌基因，引起人类T淋巴细胞的急性转化 体外。 HTLV-I诱导的白血病发生的机制尚不清楚。 这 HTLV-I和HTLV-II病毒已被分子克隆。 分析 除典型的HTLV中的核酸序列外 结构基因，一个称为x的区域，位于Env和3'长之间 末端重复（LTR）。 HTLV-I和HTLV-II X区域大约 1.6 kbp的尺寸并保留了其远端三分之二的75％ 序列。 这些高同源性X序列在HTLV-II中也是保守的 缺失突变体在具有更恶性生长的细胞中发现 特征。 最近的数据表明，实际上相同的HTLV-I和 HTLV-II高同源性X序列表示为亚基因组RNA，该序列 分别编码重40和37 kD的蛋白质。 其他研究也有 建议HTLV LTR是病毒表达的控制元素，是 通过HTLV相关因子调节了跨性别。 很可能 X编码蛋白是HTLV LTR的跨作用调节剂， 基因产物在白血病的过程中起到相似功能 通过调节遗传控制元件的正常T细胞转换 内部。 该提议的总体目标是确定是否是否 HTLV X基因产物影响HTLV LTR的行为。 具体 目的是：（1）克隆并表达HTLV-I和HTLV-II X基因； （2）确定X基因产物是否在HTLV LTR上起作用； （3） 比较HTLV-I和HTLV-II X基因产物对LTR的影响； （4）比较HTLV-I，HTLV-II和HTLV-II删除的响应 X基因产物突变ltrs； （5）确定x基因product-ltr是否 相互作用是通过各种淋巴样的细胞环境调节的 和非淋巴细胞系。 这些研究将进一步我们的理解 HTLV生物学的研究，并增加了有关机制的基本知识 病毒诱导的白血病。 目前，我的重点是 血液学恶性肿瘤和HTLV的生物学。 UCLA的环境， 有一个正在进行的计划集中在HTLV的分子生物学上 是继续我作为学术发展的理想选择 血液学家 - 研究学家。