Laderoute Keith R, Amin Khalid, Calaoagan Joy M, Knapp Merrill, Le Theresamai, Orduna Juan, Foretz Marc, Viollet Benoit
SRI International, Bldg. L, Rm. A258, 333 Ravenswood Ave., Menlo Park, CA 94025, USA.
Mol Cell Biol. 2006 Jul;26(14):5336-47. doi: 10.1128/MCB.00166-06.
Low oxygen gradients (hypoxia and anoxia) are important determinants of pathological conditions under which the tissue blood supply is deficient or defective, such as in solid tumors. We have been investigating the relationship between the activation of hypoxia-inducible factor 1 (HIF-1), the primary transcriptional regulator of the mammalian response to hypoxia, and 5'-AMP-activated protein kinase (AMPK), another regulatory system important for controlling cellular energy metabolism. In the present study, we used mouse embryo fibroblasts nullizygous for HIF-1alpha or AMPK expression to show that AMPK is rapidly activated in vitro by both physiological and pathophysiological low-oxygen conditions, independently of HIF-1 activity. These findings imply that HIF-1 and AMPK are components of a concerted cellular response to maintain energy homeostasis in low-oxygen or ischemic-tissue microenvironments. Finally, we used transformed derivatives of wild-type and HIF-1alpha- or AMPKalpha-null mouse embryo fibroblasts to determine whether AMPK is activated in vivo. We obtained evidence that AMPK is activated in authentic hypoxic tumor microenvironments and that this activity overlaps with regions of hypoxia detected by a chemical probe. We also showed that AMPK is important for the growth of this tumor model.
低氧梯度（缺氧和无氧）是病理状况的重要决定因素，在这些病理状况下，组织血液供应不足或存在缺陷，比如实体瘤。我们一直在研究缺氧诱导因子1（HIF-1）（哺乳动物对缺氧反应的主要转录调节因子）的激活与5'-AMP激活蛋白激酶（AMPK）（另一个对控制细胞能量代谢很重要的调节系统）之间的关系。在本研究中，我们使用了HIF-1α或AMPK表达缺失的小鼠胚胎成纤维细胞，以表明在体外，AMPK在生理和病理生理低氧条件下均能快速激活，且独立于HIF-1活性。这些发现意味着HIF-1和AMPK是细胞协同反应的组成部分，以在低氧或缺血组织微环境中维持能量稳态。最后，我们使用野生型以及HIF-1α或AMPKα缺失的小鼠胚胎成纤维细胞的转化衍生物来确定AMPK在体内是否被激活。我们获得的证据表明，AMPK在真实的缺氧肿瘤微环境中被激活，并且这种活性与化学探针检测到的缺氧区域重叠。我们还表明，AMPK对该肿瘤模型的生长很重要。
