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首页> 外文期刊>Biochimica et biophysica acta: international journal of biochemistry and biophysics >Sphingosine kinase, sphingosine-1-phosphate, and apoptosis.
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Sphingosine kinase, sphingosine-1-phosphate, and apoptosis.

机译：鞘氨醇激酶，鞘氨醇-1-磷酸和细胞凋亡。

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The sphingolipid metabolites ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P) play an important role in the regulation of cell proliferation, survival, and cell death. Cer and Sph usually inhibit proliferation and promote apoptosis, while the further metabolite S1P stimulates growth and suppresses apoptosis. Because these metabolites are interconvertible, it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determines cell fate. The relevance of this "sphingolipid rheostat" and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations. A central finding of these studies is that Sph kinase (SphK), the enzyme that phosphorylates Sph to form S1P, is a critical regulator of the sphingolipid rheostat, as it not only produces the pro-growth, anti-apoptotic messenger S1P, but also decreases levels of pro-apoptotic Cer and Sph. Given the role of the sphingolipid rheostat in regulating growth and apoptosis, it is not surprising that sphingolipid metabolism is often found to be disregulated in cancer, a disease characterized by enhanced cell growth, diminished cell death, or both. Anticancer therapeutics targeting SphK are potentially clinically relevant. Indeed, inhibition of SphK has been shown to suppress gastric tumor growth [Cancer Res. 51 (1991) 1613] and conversely, overexpression of SphK increases tumorigenicity [Curr. Biol. 10 (2000) 1527]. Moreover, S1P has also been shown to regulate angiogenesis, or new blood vessel formation [Cell 99 (1999) 301], which is critical for tumor progression. Furthermore, there is intriguing new evidence that S1P can act in an autocrine and/or paracrine fashion [Science 291 (2001) 1800] to regulate blood vessel formation [J. Clin. Invest. 106 (2000) 951]. Thus, SphK may not only protect tumors from apoptosis, it may also increase their vascularization, further enhancing growth. The cytoprotective effects of SphK/S1Pmay also be important for clinical benefit, as S1P has been shown to protect oocytes from radiation-induced cell death in vivo [Nat. Med. 6 (2000) 1109]. Here we review the growing literature on the regulation of SphK and the role of SphK and its product, S1P, in apoptosis.
机译：鞘脂代谢产物神经酰胺（Cer），鞘氨醇（Sph）和鞘氨醇-1-磷酸（S1P）在调节细胞增殖，存活和细胞死亡中起重要作用。 Cer和Sph通常抑制增殖并促进凋亡，而其他代谢产物S1P则刺激生长并抑制凋亡。由于这些代谢物是可相互转换的，因此提出了决定这些细胞命运的不是这些代谢物的绝对量，而是它们的相对水平。这种“鞘脂变阻剂”的相关性及其在调节细胞命运中的作用已在许多实验室中通过使用许多不同细胞类型和实验操作的工作得到证实。这些研究的主要发现是，Sph激酶（SphK）是使Sph磷酸化以形成S1P的酶，是鞘脂变阻器的关键调节剂，因为它不仅产生促生长的抗凋亡信使S1P，而且还产生降低促凋亡Cer和Sph的水平。考虑到鞘脂变阻剂在调节生长和凋亡中的作用，通常在癌症中发现鞘脂代谢被失调，该疾病以细胞生长增强，细胞死亡减少或两者兼有为特征。靶向SphK的抗癌治疗药物可能与临床相关。实际上，已显示抑制SphK可抑制胃肿瘤的生长[Cancer Res。 51（1991）1613]，反之，SphK的过度表达会增加致瘤性[Curr。Chem。（1991）1613]。生物学10（2000）1527]。此外，S1P还显示出调节血管生成或新血管形成的作用[Cell 99（1999）301]，这对肿瘤的进展至关重要。此外，有有趣的新证据表明S1P可以自分泌和/或旁分泌的方式发挥作用[Science 291（2001）1800]以调节血管的形成[J. Chem。临床投资。 106（2000）951]。因此，SphK不仅可以保护肿瘤免于凋亡，还可以增加其血管形成，进一步促进生长。 SphK / S1P的细胞保护作用对于临床获益也可能很重要，因为已经证明S1P在体内保护卵母细胞免受放射线诱导的细胞死亡[Nat。Nat。Acad.Sci。，USA，88，1897]。中6（2000）1109]。在这里，我们回顾了有关SphK调控以及SphK及其产物S1P在细胞凋亡中的作用的文献。

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