Parathyroid hormone-related protein regulates integrin α6 and β4 levels via transcriptional and post-translational pathways.
Parathyroid hormone-related protein regulates integrin α6 and β4 levels via transcriptional and post-translational pathways.
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DOI：
10.1016/j.yexcr.2013.03.003
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发表时间：
2013-06-10
影响因子：
3.7
通讯作者：
Falzon, Miriam
中科院分区：
文献类型：
--
作者：
Bhatia, Vandanajay;Mula, Ramanjaneya V. R.;Falzon, Miriam
甲状旁腺激素相关蛋白（PTHrP）在体内促进前列腺癌（CaP）生长和转移。PTHrP还能增加细胞的存活和迁移，上调促侵袭性整合素α6β4的表达。我们以人CaP细胞系C4-2和PC-3为模型系统，研究PTHrP调控α6 - β4水平的机制。我们报道PTHrP通过转录途径调节α6和β4的水平；β4的调控涉及NF-κB通路。PTHrP还在翻译后水平调控β4水平。PTHrP抑制caspase-3和- 7活性。PTHrP对β4的翻译后调控是通过这些半胱天冬酶对其蛋白水解裂解的衰减来介导的。由于α6与β4二聚，β4水平升高导致α6水平升高。利用siRNA抑制β4可减弱caspase对凋亡和细胞迁移的抑制作用。这些结果为PTHrP、整合素α6（34）水平作为caspase活性的功能与细胞存活和迁移之间的联系提供了证据。在CaP癌症中靶向PTHrP，从而逆转对caspase活性和α6β4水平的影响，可能证明在治疗上是有益的。
Parathyroid hormone-related protein (PTHrP) enhances prostate cancer (CaP) growth and metastasis in vivo. PTHrP also increases cell survival and migration, and upregulates pro-invasive integrin α6β4 expression. We used the human CaP cell lines C4-2 and PC-3 as model systems to study the mechanisms via which PTHrP regulates α6β4 levels. We report that PTHrP regulates α6 and β4 levels via a transcriptional pathway; β4 regulation involves the NF-κB pathway. PTHrP also regulates β4 levels at the post-translational level. PTHrP inhibits caspase-3 and −7 activities. Post-translational regulation of β4 by PTHrP is mediated via attenuation of its proteolytic cleavage by these caspases. Since α6 dimerizes with β4, increased β4 levels result in elevated α6 levels. Suppressing β4 using siRNA attenuates the effect of caspase inhibition on apoptosis and cell migration. These results provide evidence of a link between PTHrP, integrin α6(34 levels as a function of caspase activity, and cell survival and migration. Targeting PTHrP in CaP cancer, thereby reversing the effect on caspase activity and α6β4 levels, may thus prove therapeutically beneficial.
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影响因子：
3.7
作者：
Shen, Xiaoli;Falzon, Miriam
通讯作者：
Falzon, Miriam
DOI：
10.1016/j.bbrc.2004.11.162
发表时间：
2005-02-11
影响因子：
3.1
作者：
Deftos, LJ;Barken, I;Geller, J
通讯作者：
Geller, J
影响因子：
4.8
作者：
Gambaletta, D;Marchetti, A;Falcioni, R
通讯作者：
Falcioni, R
影响因子：
4.8
作者：
Han, ZY;Hendrickson, EA;Wyche, JH
通讯作者：
Wyche, JH
影响因子：
46.9
作者：
Schreiber, Stuart L.;Shamji, Alykhan F.;Clemons, Paul A.;Hon, Cindy;Koehler, Angela N.;Munoz, Benito;Palmer, Michelle;Stern, Andrew M.;Wagner, Bridget K.;Powers, Scott;Lowe, Scott W.;Guo, Xuecui;Krasnitz, Alex;Sawey, Eric T.;Sordella, Raffaella;Stein, Lincoln;Trotman, Lloyd C.;Califano, Andrea;Dalla-Favera, Riccardo;Ferrando, Adolfo;Iavarone, Antonio;Pasqualucci, Laura;Silva, Jose;Stockwell, Brent R.;Hahn, William C.;Chin, Lynda;DePinho, Ronald A.;Boehm, Jesse S.;Gopal, Shuba;Huang, Alan;Root, David E.;Weir, Barbara A.;Gerhard, Daniela S.;Zenklusen, Jean Claude;Roth, Michael G.;White, Michael A.;Minna, John D.;MacMillan, John B.;Posner, Bruce A.
通讯作者：
Posner, Bruce A.