Gabet Anne-Sophie, Mortreux Franck, Charneau Pierre, Riou Patrice, Duc-Dodon Madeleine, Wu Yalin, Jeang Kuan-Teh, Wattel Eric
Unité d'Oncogenèse Virale-CNRS UMR 5537, Centre Léon Bérard, 28 rue Laennec, 69373 Lyon cedex 08, France.
Oncogene. 2003 Jun 12;22(24):3734-41. doi: 10.1038/sj.onc.1206468.
Telomerase expression is the hallmark of tumor cells in which this ribonucleoprotein complex preserves chromosome integrity by maintaining telomere length and thereby prevents cell death. However, recent data support a role of the combination of p53 and telomerase inactivation in initiating genetic instability that promotes malignant transformation. Through its pleiotropic effects on infected T-cell metabolism, the human T-cell leukemia virus type 1 (HTLV-1) oncoprotein Tax plays a central role in leukemogenesis. Here, we show that Tax inhibits human telomerase reverse transcriptase (hTERT) transcription, which is the rate-limiting factor of telomerase activity. This inhibitory effect, that occurs in competition with c-Myc through a canonical c-Myc binding site within the hTERT promoter, results in a decreased telomerase activity of Tax-expressing cells. This is the first demonstration of hTERT inhibition by an oncogene. Tax, which is only expressed in preleukemic cells, triggers infected T-cell cycle and keeps these cells cycling while inactivating p53. We propose that, in combination with these effects, hTERT repression by Tax at an early phase of carcinogenesis might contribute to the massive ploidy changes associated with the development of HTLV-1-associated malignancies.
端粒酶表达是肿瘤细胞的标志，在肿瘤细胞中这种核糖核蛋白复合物通过维持端粒长度来保持染色体完整性，从而防止细胞死亡。然而，最近的数据支持p53和端粒酶失活的组合在引发促进恶性转化的基因不稳定中所起的作用。通过对受感染T细胞代谢的多效性作用，人类T细胞白血病病毒1型（HTLV-1）癌蛋白Tax在白血病发生中起核心作用。在这里，我们表明Tax抑制人类端粒酶逆转录酶（hTERT）转录，而hTERT转录是端粒酶活性的限速因素。这种抑制作用通过hTERT启动子内的一个典型c-Myc结合位点与c-Myc竞争而发生，导致表达Tax的细胞端粒酶活性降低。这是癌基因对hTERT抑制作用的首次证明。仅在白血病前期细胞中表达的Tax触发受感染T细胞周期，并使这些细胞持续循环，同时使p53失活。我们提出，结合这些作用，Tax在致癌作用早期对hTERT的抑制可能导致与HTLV-1相关恶性肿瘤发展相关的大量倍性变化。
