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Regulation of cell proliferation and cell density by the inorganic phosphate transporter PiT1

机译：无机磷酸盐转运蛋白粘合剂的细胞增殖和细胞密度调节

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Background The inorganic phosphate (Pi) transporter, PiT1 (SLC20A1), is ubiquitously expressed in mammalian cells. It has previously been shown that down-regulation of PiT1 severely impaired the proliferation of two transformed human cells lines, HepG2 and HeLa, and the tumorigenicity of HeLa cells in nude mice. Moreover, PiT1 knock-out mice do not survive past E12.5 and from E10.5, the embryos were found to be growth-retarded and showed reduced proliferation of liver cells. Isolated mouse embryonic fibroblasts with knocked out as well as reduced PiT1 expression levels also exhibited impaired proliferation. Together these results suggest that a certain level of PiT1 is important for proliferation. We have here investigated the role of PiT1 in regulation of cell proliferation using two strictly density-inhibited cells lines, the murine MC3T3-E1 and NIH3T3 cells. Results We found that knock-down of PiT1 in MC3T3-E1 cells led to impaired proliferation supporting that at least a certain level of PiT1 is important for wildtype level of proliferation. We, however, also observed that MC3T3-E1 and NIH3T3 cells themselves regulate their endogenous PiT1 mRNA levels with lower levels in general correlating with decreased proliferation/increased cell density. Moreover, over-expression of human PiT1 led to increased proliferation of both MC3T3-E1 and NIH3T3 cultures and resulted in higher cell densities in cultures of these two strictly density-inhibited cell lines. In addition, when we transformed NIH3T3 cells by cultivation in fetal bovine serum, cells over-expressing human PiT1 formed more colonies in soft agar than control cells. Conclusions We conclude that not only is a certain level of PiT1 necessary for normal cell division as suggested by previously published studies, rather the cellular PiT1 level is involved in regulating cell proliferation and cell density and an increased PiT1 expression can indeed make NIH3T3 cells more sensitive to transformation. We have thus provided the first evidence for that expression of the type III Pi transporter, PiT1, above the endogenous level can drive cell proliferation and overrule cell density constraints, and the results bridge previous observations showing that a certain PiT1 level is important for regulating normal embryonic growth/development and for tumorigenicity of HeLa cells.
机译：背景技术无机磷酸盐（P i ）转运蛋白，PIT1（SLC20A1）在哺乳动物细胞中普遍地表达。先前已经表明，PIT1的下调严重受损了两种转化的人细胞系，HepG2和Hela的增殖，以及裸鼠中HeLa细胞的致瘤性。此外，PIT1敲除小鼠不会在E12.5和E10.5过去生存，发现胚胎被生长延迟并显示出肝细胞的增殖降低。孤立的小鼠胚胎成纤维细胞与敲除来以及降低的pit1表达水平也表现出增殖受损。这些结果表明，一定程度的PIT1对扩散很重要。我们在这里研究了PIT1在使用两个严格密度抑制细胞系，鼠MC3T3-E1和NIH3T3细胞调节细胞增殖调节中的作用。结果发现，MC3T3-E1细胞中PIT1的击倒导致增殖损害，支持至少一定水平的PIT1对野生型增殖水平很重要。然而，我们还观察到MC3T3-E1和NIH3T3细胞本身在与细胞密度降低的情况下，将其内源性PIT1 mRNA水平调节，其具有较低的水平。此外，人pit1的过表达导致MC3T3-E1和NIH3T3培养物的增殖增加，并导致这两个严格密度抑制细胞系的培养物中的更高细胞密度。此外，当我们通过胎儿牛血清培养转化NiH3T3细胞时，在软琼脂上呈现出更多的细胞比对照细胞形成更多的菌落。结论我们得出结论，正常细胞划分的不仅是由先前公布的研究所提出的正常细胞划分所必需的一定程度的PIT1，而是蜂窝PIT1水平参与调节细胞增殖和细胞密度，并且增加的PIT1表达可以确实使NIH3T3细胞更敏感转变。因此，我们提供了第一个证据表达III型表达III P I Transporter，PIT1，高于内源水平可以驱动细胞增殖和溢出细胞密度约束，并且结果桥接前观察结果某些PIT1水平对于调节正常胚胎生长/发育和Hela细胞的致瘤性是重要的。

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