PDF(Pubmed)
Abstract：
Rapidly proliferative processes in mammalian tissues including tumorigenesis and embryogenesis rely on the glycolytic pathway for energy and biosynthetic precursors. The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) plays an important regulatory role in glycolysis by activating the key rate-limiting glycolytic enzyme, 6-phosphofructo-1-kinase (PFK-1). We have previously determined that decreased PFKFB3 expression reduced glycolysis and growth in transformed cells in vitro and suppressed xenograft growth in vivo. In earlier studies, we created a constitutive knockout mouse to interrogate the function of PFKFB3 in vivo but failed to generate homozygous offspring due to the requirement for PFKFB3 for embryogenesis. We have now developed a novel transgenic mouse model that exhibits inducible homozygous pan-tissue Pfkfb3 gene deletion (Pfkfb3fl/fl). We have induced Pfkfb3 genomic deletion in these mice and found that it effectively decreased PFKFB3 expression and activity. To evaluate the functional consequences of Pfkfb3 deletion in vivo, we crossed Cre-bearing Pfkfb3fl/fl mice with oncogene-driven tumor models and found that Pfkfb3 deletion markedly decreased their glucose uptake and growth. In summary, our studies reveal a critical regulatory function for PFKFB3 in glycolysis and tumorigenesis in vivo and characterize an effective and powerful model for further investigation of its role in multiple biological processes.
摘要：
哺乳动物组织中的快速增殖过程包括肿瘤发生和胚胎发生依赖于能量和生物合成前体的糖酵解途径。酶6-磷酸果糖-2-激酶/果糖-2,6-双磷酸酶-3（PFKFB3）通过激活关键的限速糖酵解酶在糖酵解中起重要的调节作用，6-磷酸果糖-1-激酶(PFK-1)。我们先前已经确定降低的PFKFB3表达在体外降低了转化细胞中的糖酵解和生长,并在体内抑制了异种移植物生长。在早期的研究中，我们创建了一个组成型敲除小鼠来体内询问PFKFB3的功能，但由于胚胎发生需要PFKFB3，因此未能产生纯合后代。我们现在已经开发了一种新型转基因小鼠模型,其表现出诱导型纯合全组织Pfkfb3基因缺失(Pfkfb3fl/fl)。我们已经在这些小鼠中诱导了Pfkfb3基因组缺失，并发现它有效地降低了PFKFB3的表达和活性。为了评估体内Pfkfb3缺失的功能后果，我们将带有Cre的Pfkfb3fl/fl小鼠与癌基因驱动的肿瘤模型交叉，发现Pfkfb3缺失显着降低了其葡萄糖的摄取和生长。总之,我们的研究揭示了PFKFB3在体内糖酵解和肿瘤发生中的关键调节功能，并表征了一个有效和强大的模型，以进一步研究其在多个生物学过程中的作用。
