Neu differentiation factor (Heregulin) activates a p53-dependent pathway in cancer cells.
Neu differentiation factor (Heregulin) activates a p53-dependent pathway in cancer cells.
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发表时间：
1996-06
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影响因子：
8
通讯作者：
S. Bacus;Y. Yarden;M. Oren;D. Chin;L. Lyass;C. Zelnick;A. Kazarov;W. Toyofuku;J. Gray-Bablin;R. Beerli;N. Hynes;M. Nikiforov;R. Haffner;A. Gudkov;K. Keyomarsi
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作者：
S. Bacus;Y. Yarden;M. Oren;D. Chin;L. Lyass;C. Zelnick;A. Kazarov;W. Toyofuku;J. Gray-Bablin;R. Beerli;N. Hynes;M. Nikiforov;R. Haffner;A. Gudkov;K. Keyomarsi
此前我们曾报道，Neu分化因子(NDF)/Hereglin(HRG)通过异源二聚体的形成促进其受体erbB-3、erbB-4和erbB-2的酪氨酸磷酸化。我们还发现，NDF/HRG和针对erbB-2的抗体都可以抑制乳腺癌细胞的生长并诱导其分化。在本研究中，我们报道了NDF/HRG诱导的细胞效应的机制。我们发现NDF/HRG和针对erbB-2受体的抗体通过稳定P53蛋白来上调P53的表达。伴随而来的是p53诱导基因p21CIP1/WAF1在多种细胞系中的上调：MCF7及其衍生物(MCF7/HER2，MN1和MCF-7-Puro)，ZR75T和LNCaP细胞。当同时用NDF/HRG和DNA损伤化疗药物(即阿霉素)处理细胞时，p21的诱导进一步增强。NDF/HRG介导的p21诱导依赖于野生型p53，因为它不能发生在表达显性阴性p53(MDD2)的细胞中。此外，组蛋白H1的磷酸化实验表明，p21诱导能够使CDK2复合体失活。最后，我们发现，在乳腺癌和其他癌症的原代培养中，NDF/HRG处理显著诱导了p21的表达。总之，这些观察结果表明，通过激活erbB受体抑制和分化乳腺癌细胞的机制是通过P53介导的途径。
Previously we reported that neu differentiation factor (NDF)/heregulin (HRG) elevates tyrosine phosphorylation of its receptors erbB-3, erbB-4, and erbB-2 (through heterodimer formation). We also showed that both NDF/HRG and antibodies to erbB-2 can arrest growth and induce differentiation in breast cancer cells. In this study, we report on the mechanism of NDF/HRG-induced cellular effects. We show that NDF/HRG and antibodies to erbB-2 receptors up-regulate expression of p53 by stabilizing the protein. This is accompanied by up-regulation of the p53 inducible gene, p21CIP1/WAF1, in a variety of cell lines: MCF7 and their derivatives (MCF7/HER2, MN1 and MCF-7-puro), ZR75T and LnCap cells. The induction of p21 is further enhanced when cells are treated with both NDF/HRG and DNA-damaging chemotherapeutic agents (i.e. doxorubicin). The NDF/HRG mediated induction of p21 is dependent on wildtype p53, as it fails to occur in cells expressing dominant negative p53 (MDD2). Furthermore, p21 induction is capable of inactivating cdk2 complexes as measured by Histone H1 phosphorylation assays. Finally, we show that in primary cultures of breast and other cancers, p21 is significantly induced in response to NDF/HRG treatment. Collectively, these observations suggest that the mechanism of breast cancer cell growth inhibition and differentiation via erbB receptors activation is through a p53-mediated pathway.