Phosphorylated retinoblastoma protein complexes with pp32 and inhibits pp32-mediated apoptosis
Phosphorylated retinoblastoma protein complexes with pp32 and inhibits pp32-mediated apoptosis
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DOI：
10.1074/jbc.m411382200
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发表时间：
2005-04-22
影响因子：
4.8
通讯作者：
Pasternack, GR
中科院分区：
文献类型：
--
作者：
Adegbola, O;Pasternack, GR
视网膜母细胞瘤基因产物（Rb）是一种矛盾地影响细胞凋亡的肿瘤抑制因子。大多数散发性癌症通过优先靶向调节Rb磷酸化的途径抑制Rb，导致对凋亡的抵抗;这与突变引起的Rb失活形成对比，Rb失活与高凋亡率相关。磷酸化的Rb如何保护细胞免于凋亡还不清楚，但有证据表明Rb可能螯合促凋亡核因子。pp 32（ANP 32A）是促凋亡核磷蛋白，其表达通常在癌症中增加。我们报告，过度磷酸化Rb与pp 32相互作用，但不与密切相关的蛋白质pp 32 r1和pp 32 r2。我们进一步证明，pp 32-Rb相互作用抑制pp 32的凋亡活性，并刺激增殖。这些结果表明，当Rb被过度磷酸化灭活时，癌细胞获得增殖和存活优势的机制。
The retinoblastoma gene product (Rb) is a tumor suppressor that affects apoptosis paradoxically. Most sporadic cancers inactivate Rb by preferentially targeting the pathway that regulates Rb phosphorylation, resulting in resistance to apoptosis; this contrasts with Rb inactivation by mutation, which is associated with high rates of apoptosis. How phosphorylated Rb protects cells from apoptosis is not well understood, but there is evidence that Rb may sequester a pro-apoptotic nuclear factor. pp32 (ANP32A) is a pro-apoptotic nuclear phosphoprotein, the expression of which is commonly increased in cancer. We report that hyperphosphorylated Rb interacts with pp32 but not with the closely related proteins pp32r1 and pp32r2. We further demonstrate that pp32-Rb interaction inhibits the apoptotic activity of pp32 and stimulates proliferation. These results suggest a mechanism whereby cancer cells gain both a proliferative and survival advantage when Rb is inactivated by hyperphosphorylation.