Activation of wild type p53 function by its mortalin-binding, cytoplasmically localizing carboxyl terminus peptides
Activation of wild type p53 function by its mortalin-binding, cytoplasmically localizing carboxyl terminus peptides
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DOI：
10.1074/jbc.m500022200
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发表时间：
2005-11-25
影响因子：
4.8
通讯作者：
Wadhwa, R
中科院分区：
文献类型：
--
作者：
Kaul, SC;Aida, S;Wadhwa, R
Hsp70家族成员mortalin(mot-2/mthsp70/GRP75)与肿瘤抑制蛋白P53的羧基末端区域结合。通过体内免疫共沉淀法，我们将p53及其缺失突变体的mot-2结合位点定位在其羧基末端的312-352个氨基酸残基上。在本研究中，我们试图通过过表达短的P53羧基末端多肽来破坏MOT-2-P53的相互作用。我们报道了P53羧基末端多肽(氨基酸残基312-390、312-352、323-390和323-352)定位于细胞质中，而312-322、337-390、337-352和352-390氨基酸残基主要定位于细胞核。最有趣的是，含有323-337残基的细胞质定位的p53多肽通过将其从P53-mortalin复合体中置换出来并将其重新定位到细胞核中来激活内源性P53的功能。这种P53功能的激活足以导致人骨肉瘤和乳腺癌细胞的生长停滞。
The Hsp70 family member mortalin (mot-2/mthsp70/GRP75) binds to a carboxyl terminus region of the tumor suppressor protein p53. By in vivo co-immunoprecipitation of mot-2 with p53 and its deletion mutants, we earlier mapped the mot-2-binding site of p53 to its carboxyl terminus 312-352 amino acid residues. In the present study we attempted to disrupt mot-2-p53 interactions by overexpression of short p53 carboxyl-terminal peptides. We report that p53 carboxyl-terminal peptides ( amino acid residues 312-390, 312-352, 323-390, and 323-352) localize in the cytoplasm, whereas 312-322, 337-390, 337-352, and 352-390 locate mostly in the nucleus. Most interestingly, the cytoplasmically localizing p53 peptides harboring the residues 323-337 activated the endogenous p53 function by displacing it from p53-mortalin complexes and relocating it to the nucleus. Such activation of p53 function was sufficient to cause growth arrest of human osteosarcoma and breast carcinoma cells.