REGULATION OF APOPTOSIS BY THE RETINOID AHPN

类维生素A AHPN 对细胞凋亡的调节

• 批准号: 6289941
• 负责人: Anton M Jetten
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289941
• 关键词: biological signal transduction; enzyme activity; guanine nucleotide binding protein; human tissue; lung neoplasms; protein kinase; retinoblastoma protein; retinoid binding proteins; retinoids; tissue /cell culture

Retinoids are important regulators of development, cell growth and differentiation. Many of the effects of retinoids on gene expression are mediated through the nuclear retinoid receptors RARs and RXRs. However, the actions of certain retinoids such as retinoid 6-[3-(1- adamantyl)-4-hydroxy-phenyl]-2-naphthalene- carboxylic acid (AHPN) are not mediated by these nuclear receptors. AHPN inhibits the proliferation and induces apoptosis in many lung carcinoma and lymphoma cell lines. Flow cytometric analyses indicated that treatment of lung carcinoma H460 cells with AHPN induces G1 cell cycle arrest while it induces a G2 arrest in lymphoma cells. The induction of apoptosis is accompanied by an increase in annexin V binding and caspase-3-like activity. Overexpression of Bcl-2 inhibited the induction of apoptosis but did not block cell death. The caspase inhibitor ZVAD-fmk also inhibited cell death but did not affect the induction of growth arrest. The specificity by which AHPN and other retinoids induce growth arrest and apoptosis indicates that AHPN action is not mediated by RAR or RXR receptors but involves a novel signaling pathway. cDNA-macro array analysis identified a number of genes that are induced by AHPN. Many of these genes are involved in the control of cell growth and apoptosis. These include Egr-1, Nur77, GADD45, MyD118 and IRF-1. These genes are controlled by AHPN at both transcriptional and post-transcriptional mechanisms. Inhibition of MEK kinase but not of p38 MAPK blocks the induction of these genes by AHPN indicating that activation of the ERK MAPK signaling pathway is important in the induction of these genes by AHPN. - apoptosis, retinoids, growth control, lung carcinoma, retinoid receptors, lymphoma

类维生素A是发育、细胞生长和分化的重要调节剂。类维生素A对基因表达的许多作用是通过核类维生素A受体RAR和RXR介导的。然而，某些类维生素A如类维生素A 6-[3-（1-金刚烷基）-4-羟基-苯基]-2-萘-羧酸（AHPN）的作用不由这些核受体介导。AHPN在许多肺癌和淋巴瘤细胞系中抑制增殖并诱导凋亡。流式细胞仪分析表明，AHPN处理肺癌H460细胞诱导G1期细胞周期阻滞，而它诱导淋巴瘤细胞G2期阻滞。凋亡的诱导伴随着膜联蛋白V结合和半胱天冬酶-3样活性的增加。Bcl-2过表达抑制细胞凋亡的诱导，但不阻止细胞死亡。半胱天冬酶抑制剂ZVAD-fastin也抑制细胞死亡，但不影响生长停滞的诱导。AHPN和其他类维生素A诱导生长停滞和细胞凋亡的特异性表明AHPN的作用不是由RAR或RXR受体介导的，而是涉及一种新的信号通路。cDNA-macro array分析鉴定了AHPN诱导的许多基因。这些基因中的许多参与细胞生长和凋亡的控制。这些包括Egr-1、Nur 77、GADD 45、MyD 118和IRF-1。这些基因是由AHPN在转录和转录后机制控制。抑制MEK激酶而不是p38 MAPK阻断了AHPN对这些基因的诱导，表明ERK MAPK信号通路的激活在AHPN对这些基因的诱导中是重要的。- 凋亡，维甲酸，生长调控，肺癌，维甲酸受体，淋巴瘤