Elucidation of the mechanism of hyperactivation of p53 lacking C terminal domain

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08202
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: University of Yamanashi
• Principal Investigator: Nakane Takaya 山梨大学, 大学院総合研究部, 医学研究員 (90422683)
• Co-Investigator(Kenkyū-buntansha): 矢ヶ崎 英晃 山梨大学, 大学院総合研究部, 特任講師 (00377540) ; 成澤 宏宗 山梨大学, 大学院総合研究部, 臨床助教 (70808013)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: p53

Outline of Final Research Achievements

Mutants lacking the carboxyl terminal (CTD) of p53 lack the MDM2/4 binding site and results in p53 hyperactivation; mouse homozygotes carrying p53 lacking CTD have severe bone marrow failure and die early. To examine the relationship between the extent of CTD deletion in p53 and phenotype, we generated two types of gene-edited mice with incomplete and complete deletion of the CTD. In addition, using K562 cells transfected with wild-type p53 and p53 lacking CTD, the effect of CTD in p53 on hemin-induced erythroid differentiation was examined by measuring hemoglobin positive cells. We found that, first, partial CTD deletion caused much severer phenotype than complete CTD deletion did, and the male sterility was found in mice with incomplete CTD deletion for the first time, second, p53 lacking CTD mutations in two alleles are additive in severity of the pehnotype, third, CTD of p53 acts in a promotive manner with respect to erythroid-like cell differentiation effects.

Free Research Field

小児科学

Academic Significance and Societal Importance of the Research Achievements

CTDのp53機能制御メカニズムへの関与を明らかにしたことは、p53の機能低下・亢進で生じるがんや骨髄形成不全などの治療法の開発に役立つ。P53のCTD欠失ヘテロマウスでの雄性不妊発見は、ヒトでもp53のCTD欠失が男性不妊の原因である可能性を示し、新たな病態の解明や治療法の開発に資する。P53のK562細胞に対する赤血球様分化にCTDが促進的に作用していることの解明は、K562が慢性白血病細胞から樹立された細胞株であることを鑑みれば、p53のCTD分子や、CTDに対する抗体などを用いた腫瘍細胞の治療法開発に役立つ。