PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanisms in haematological malignancies
PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanisms in haematological malignancies
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DOI：
10.1093/hmg/8.2.185
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发表时间：
1999-02-01
影响因子：
3.5
通讯作者：
Eng, C
中科院分区：
文献类型：
--
作者：
Dahia, PLM;Aguiar, RCT;Eng, C
PTEN是一种新的肿瘤抑制基因，其编码与粘附分子张力蛋白和生长素具有同源性的双特异性磷酸酶。最近已经提出，PTEN使磷脂酰肌醇3，4，5-三磷酸[PtdIns（3，4，5）P-3]去磷酸化，其介导生长因子诱导的细胞内信号传导的激活，特别是通过丝氨酸-苏氨酸激酶Akt，一种已知的细胞存活促进因子，PTEN已被定位于10q23.3，这是一个在包括血液恶性肿瘤在内的几种人类肿瘤中被破坏的区域。我们分析了一系列原发性急性白血病和非霍奇金淋巴瘤（NHL）以及细胞系中的PTEN。我们还研究了在这些样品中是否可以发现PTEN和Akt水平之间的相关性。我们在这里表明，大多数研究的细胞系携带PTEN异常。在结构水平上，我们发现40%的这些细胞系中存在突变和半合子缺失，而少数原发性血液恶性肿瘤，特别是NHL，携带PTEN突变。此外，三分之一的细胞系具有低的PTEN转录物水平，并且这些样品中的60%具有低的或不存在的PTEN蛋白，这不能归因于通过超甲基化的基因沉默。此外，我们发现在绝大多数检查的样品中，PTEN和磷酸化Akt水平呈负相关。这些发现表明，PTEN在血液恶性肿瘤的发病机制中起作用，并且它可能通过比最初考虑的更广泛的机制被灭活。PTEN水平与磷酸化Akt负相关的发现支持了PTEN调节PtdIns（3，4，5）P-3的假设，并表明了PTEN在细胞凋亡中的作用。
PTEN is a novel tumour suppressor gene that encodes a dual-specificity phosphatase with homology to adhesion molecules tensin and auxillin, It recently has been suggested that PTEN dephosphorylates phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P-3], which mediates growth factor-induced activation of intracellular signalling, in particular through the serine-threonine kinase Akt, a known cell survival-promoting factor, PTEN has been mapped to 10q23.3, a region disrupted in several human tumours including haematological malignancies. We have analysed PTEN in a series of primary acute leukaemias and non-Hodgkin's lymphomas (NHLs) as well as in cell lines. We have also examined whether a correlation could be found between PTEN and Akt levels in these samples. We show here that the majority of cell lines studied carries PTEN abnormalities. At the structural level, we found mutations and hemizygous deletions in 40% of these cell lines, while a smaller number of primary haematological malignancies, in particular NHLs, carries PTEN mutations. Moreover, one-third of the cell lines had low PTEN transcript levels, and 60% of these samples had low or absent PTEN protein, which could not be attributed to gene silencing by hypermethylation, In addition, we found that PTEN and phosphorylated Akt levels are inversely correlated in the large majority of the examined samples. These findings suggest that PTEN plays a role in the pathogenesis of haematological malignancies and that it might be inactivated through a wider range of mechanisms than initially considered. The finding that PTEN levels inversely correlate with phosphorylated Akt supports the hypothesis that PTEN regulates PtdIns(3,4,5)P-3 and suggests a role for PTEN in apoptosis.