Khaleque Md Abdul, Bharti Ajit, Sawyer Douglas, Gong Jianlin, Benjamin Ivor J, Stevenson Mary Ann, Calderwood Stuart K
Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Oncogene. 2005 Sep 29;24(43):6564-73. doi: 10.1038/sj.onc.1208798.
Elevation of heat shock protein (HSP) levels is widespread in cancer and predicts a poor prognosis and resistance to therapy. We show that HSP elevation in tumor cells can be induced by the highly malignant factor heregulin beta1 (HRGbeta1), which induces HSP expression through heat shock transcription factor 1 (HSF1). Inactivation of the hsf1 gene prevents HSP induction by HRGbeta1. HSP expression is induced through a cascade response initiated by HRGbeta1 binding to c-erbB receptors on the cell surface and which leads to the inhibition of intracellular HSF1 antagonist glycogen synthase kinase 3. HSF1 activated by this pathway plays a key role in the protection of cells from apoptosis and the mediation of anchorage independent growth by HRGbeta1, indicating a role for HSF1 in this tumorigenic pathway.
热休克蛋白（HSP）水平升高在癌症中广泛存在，并预示着预后不良和对治疗的抵抗。我们发现肿瘤细胞中HSP水平的升高可由高恶性因子神经调节蛋白β1（HRGβ1）诱导，HRGβ1通过热休克转录因子1（HSF1）诱导HSP表达。hsf1基因的失活可阻止HRGβ1诱导HSP。HSP表达是通过HRGβ1与细胞表面c-erbB受体结合引发的级联反应诱导的，该反应导致细胞内HSF1拮抗剂糖原合酶激酶3的抑制。通过该途径激活的HSF1在保护细胞免受凋亡以及HRGβ1介导的不依赖贴壁生长中起关键作用，表明HSF1在该致癌途径中发挥作用。
