Differential modulation of plasminogen activator gene expression by oncogene-encoded protein tyrosine kinases.
Differential modulation of plasminogen activator gene expression by oncogene-encoded protein tyrosine kinases.
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癌基因编码的蛋白酪氨酸激酶对纤溶酶原激活剂基因表达的差异调节。
DOI：
10.1128/mcb.13.9.5888-5897.1993
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发表时间：
1993
影响因子：
5.3
通讯作者：
Degen,JL
中科院分区：
文献类型：
--
作者：
Bell,SM;Connolly,DC;Maihle,NJ;Degen,JL
酪氨酸蛋白激酶pp60v-src转化鸡胚成纤维细胞（CEF）后，尿激酶型纤溶酶原激活物（uPA）基因转录增加≥50倍。在这些细胞中，蛋白磷酸化似乎在uPA基因表达中起关键作用；蛋白激酶c激活phorbol酯与pp60v- src协同增加uPA mRNA，而环AMP （cAMP）依赖性蛋白激酶激活剂（例如8-溴cAMP）抑制uPA mRNA水平。为了探讨转化癌基因与uPA基因表达之间的关系，我们检测了经禽类逆转录病毒感染的CEF中uPA mRNA的表达水平。我们报道v-rasa和转化蛋白酪氨酸激酶v-src、v-yes和v-rosall增加细胞uPA mrna。然而，用v-erbB编码的蛋白酪氨酸激酶或v-jun、v-ski或v-myc编码的核蛋白转化，并没有明显增加uPA mRNA。分析了Ras和所有酪氨酸蛋白激酶，包括v- erbb产物，但没有核癌蛋白使细胞对磷酸酯诱导的uPA基因表达敏感。因此，uPA基因表达的增加不仅仅是细胞转化的次要后果，而是仅由一部分癌基因产物调节或调节。对表达pp60v-src位点定向突变体的细胞的分析表明，uPA基因的诱导依赖于蛋白酪氨酸激酶的催化活性、肉豆芽化和质膜定位。然而，这些性质加在一起是不够的；还需要血液学领域的附加功能。丝氨酸磷酸化的主要位点，丝氨酸12和17，以及自磷酸化位点，酪氨酸416，对于uPA基因诱导不是必需的。然而，8-溴cAMP对pp60v-src转化细胞中uPA mRNA的减少依赖于酪氨酸416。
Urokinase-type plasminogen activator (uPA) gene transcription is increased ≥ = 50-fold in chicken embryo fibroblasts (CEF) following transformation by the protein tyrosine kinase pp60v-src. Protein phosphorylation appears to play a critical role in uPA gene expression in these cells; protein kinase C-activating phorbol esters cooperate with pp60v-srcto synergistically increase uPA mRNA, whereas cyclic AMP (cAMP)-dependent protein kinase-activating agents (e.g., 8-bromo cAMP) repress uPA mRNA levels. To explore the relationship between transforming oncogenes and uPA gene expression, uPA mRNA levels were measured in CEF infected with selected avian retroviruses. We report that v-rasand the transforming protein tyrosine kinases v-src, v-yes, and v-rosall increase cellular uPA mRNAs. However, transformation with the protein tyrosine kinase encoded by v-erbB, or the nuclear proteins encoded by v-jun, v-ski, or v-myc, did not increase uPA mRNA detectably. Ras and all of the protein tyrosine kinases analyzed, including the v-erbBproduct, but none of the nuclear oncoproteins sensitized cells to phorbol ester induction of uPA gene expression. Thus, increased uPA gene expression is not simply a secondary consequence of cell transformation but, rather, is regulated or comodulated by only a subset of oncogene products. Analysis of cells expressing site-directed mutants of pp60v-srcshowed that the induction of the uPA gene is dependent on protein tyrosine kinase catalytic activity, myristylation, and plasma membrane localization. However, these properties together are not sufficient; an additional feature in thesrchomology 2 domain is also required. The major sites of serine phosphorylation, serines 12 and 17, and the autophosphorylation site, tyrosine 416, are not essential for uPA gene induction. However, the reduction of uPA mRNA in pp60v-src-transformed cells by 8-bromo cAMP is dependent on tyrosine 416.