Crowe David L, Nguyen Dan C, Ohannessian Arthur
Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
Int J Oncol. 2005 Sep;27(3):847-54.
Stratified squamous epithelial cells undergo an orderly process of cell cycle arrest following detachment from the basement membrane. The basal layer cells which adhere to the basement membrane express telomerase, which maintains the ends of chromosomes in this rapidly dividing population. Non-dividing suprabasal cells downregulate telomerase activity. However, the mechanisms regulating this inhibition are unknown. We examined the regulation of telomerase expression in anchorage-deprived normal human epidermal keratinocytes and squamous cell carcinoma lines. Anchorage-deprived cells underwent rapid loss of telomerase activity. Attachment loss was associated with increased ERK1 activity, G1 to S phase progression, and subsequent G2 arrest. Adhesion to collagen via specific integrin subunits inhibited ERK1 activity and telomerase repression. Loss of telomerase expression was associated with recruitment of an Rb/HDAC1 repressor complex to the -98 E2F site of the hTERT promoter. We propose a mechanism by which anchorage deprivation inhibits telomerase activity in stratified squamous epithelial cells and squamous cell carcinoma lines.
分层鳞状上皮细胞从基底膜脱离后会经历一个有序的细胞周期停滞过程。附着于基底膜的基底层细胞表达端粒酶，该酶维持这个快速分裂群体中染色体的末端。不分裂的基底上层细胞下调端粒酶活性。然而，调节这种抑制作用的机制尚不清楚。我们研究了在脱离锚定的正常人表皮角质形成细胞和鳞状细胞癌系中端粒酶表达的调控。脱离锚定的细胞端粒酶活性迅速丧失。失去附着与ERK1活性增加、从G1期到S期进展以及随后的G2期停滞有关。通过特定整合素亚基与胶原蛋白的黏附抑制了ERK1活性和端粒酶抑制。端粒酶表达的丧失与Rb/HDAC1阻遏复合物募集到hTERT启动子的-98 E2F位点有关。我们提出了一种机制，通过该机制脱离锚定抑制分层鳞状上皮细胞和鳞状细胞癌系中的端粒酶活性。
