Horikawa Izumi, Barrett J Carl
Laboratory of Biosystems and Cancer, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 37, Room 5046, MSC-4264, Bethesda, MD 20892, USA.
Carcinogenesis. 2003 Jul;24(7):1167-76. doi: 10.1093/carcin/bgg085. Epub 2003 May 22.
Malignant transformation from mortal, normal cells to immortal, cancer cells is generally associated with activation of telomerase and subsequent telomere maintenance. A major mechanism to regulate telomerase activity in human cells is transcriptional control of the telomerase catalytic subunit gene, human telomerase reverse transcriptase (hTERT). Several transcription factors, including oncogene products (e.g. c-Myc) and tumor suppressor gene products (e.g. WT1 and p53), are able to control hTERT transcription when over-expressed, although it remains to be determined whether a cancer-associated alteration of these factors is primarily responsible for the hTERT activation during carcinogenic processes. Microcell-mediated chromosome transfer experiments have provided evidence for endogenous factors that function to repress the telomerase activity in normal cells and are inactivated in cancer cells. At least one of those endogenous telomerase repressors, which is encoded by a putative tumor suppressor gene on chromosome 3p, acts through transcriptional repression of the hTERT gene. The hTERT gene is also a target site for viruses frequently associated with human cancers, such as human papillomavirus (HPV) and hepatitis B virus (HBV). HPV E6 protein contributes to keratinocyte immortalization and carcinogenesis through trans-activation of the hTERT gene transcription. In at least some hepatocellular carcinomas, the hTERT gene is a non-random integration site of HBV genome, which activates in cis the hTERT transcription. Thus, a variety of cellular and viral oncogenic mechanisms converge on transcriptional control of the hTERT gene. Regulation of chromatin structure through the modification of nucleosomal histones may mediate the action of these cellular and viral mechanisms. Further elucidation of the hTERT transcriptional regulation, including identification and characterization of the endogenous repressor proteins, should lead to better understanding of the complex regulation of human telomerase in normal and cancer cells and may open up new strategies for anticancer therapy.
从有寿命的正常细胞向永生的癌细胞的恶性转化通常与端粒酶的激活及随后的端粒维持有关。在人类细胞中调节端粒酶活性的一个主要机制是对端粒酶催化亚基基因——人类端粒酶逆转录酶（hTERT）的转录控制。几种转录因子，包括癌基因产物（如c-Myc）和肿瘤抑制基因产物（如WT1和p53），在过度表达时能够控制hTERT转录，尽管这些因子与癌症相关的改变是否在致癌过程中主要负责hTERT激活仍有待确定。微细胞介导的染色体转移实验为内源性因子提供了证据，这些内源性因子在正常细胞中发挥抑制端粒酶活性的作用，而在癌细胞中失活。这些内源性端粒酶抑制因子中至少有一个由3号染色体短臂上的一个假定肿瘤抑制基因编码，通过对hTERT基因的转录抑制发挥作用。hTERT基因也是经常与人类癌症相关的病毒的靶位点，如人乳头瘤病毒（HPV）和乙型肝炎病毒（HBV）。HPV E6蛋白通过hTERT基因转录的反式激活促进角质形成细胞的永生和致癌作用。在至少一些肝细胞癌中，hTERT基因是HBV基因组的一个非随机整合位点，它顺式激活hTERT转录。因此，多种细胞和病毒致癌机制都集中在对hTERT基因的转录控制上。通过核小体组蛋白修饰对染色质结构的调节可能介导这些细胞和病毒机制的作用。进一步阐明hTERT转录调控，包括鉴定和表征内源性抑制蛋白，应该会导致对正常细胞和癌细胞中人类端粒酶复杂调控的更好理解，并可能为抗癌治疗开辟新策略。
