摘要
The tumor suppressor p53 protein is either lost or mutated in about half of all human cancers.Loss of p53 function is well known to influence cell spreading,migration and invasion.While expression of mutant p53 is not equivalent to p53 loss,mutant p53 can acquire new functions to drive cell spreading and migration via different mechanisms.In our study,we found that mutant p53 significantly increased cell spreading and migration when comparing with p53-null cells.RNA-Seq analysis suggested that Rho GTPase activating protein 44(ARHGAP44) is a new target of mutant p53,which suppressed AKHGAP44 transcription.ARHGAP44 has GAP activity and catalyze GTP hydrolysis on Cdc42.Higher level of GTP-Cdc42 was correlated with increase expression of mutant p53 and reduced ARHGAP44.Importantly,wt-ARHGAP44 but not mutant ARHGAP44(R291A) suppressed mutant p53 mediated cell spreading and migration.Bioinformatics analysis indicated lower expression of ARHGAP44 in lung carcinoma compared with normal tissues,which was verified by RT-qPCR using specimens from patients.More interestingly,ARHGAP44 mRNA level was lower in tumors with mutant p53 than those with normal p53.Collectively,our results disclose a new mechanism by which mutant p53 stimulates cell spreading and migration.
The tumor suppressor p53 protein is either lost or mutated in about half of all human cancers.Loss of p53 function is well known to influence cell spreading,migration and invasion.While expression of mutant p53 is not equivalent to p53 loss,mutant p53 can acquire new functions to drive cell spreading and migration via different mechanisms.In our study,we found that mutant p53 significantly increased cell spreading and migration when comparing with p53-null cells.RNA-Seq analysis suggested that Rho GTPase activating protein 44（ARHGAP44） is a new target of mutant p53,which suppressed AKHGAP44 transcription.ARHGAP44 has GAP activity and catalyze GTP hydrolysis on Cdc42.Higher level of GTP-Cdc42 was correlated with increase expression of mutant p53 and reduced ARHGAP44.Importantly,wt-ARHGAP44 but not mutant ARHGAP44（R291A） suppressed mutant p53 mediated cell spreading and migration.Bioinformatics analysis indicated lower expression of ARHGAP44 in lung carcinoma compared with normal tissues,which was verified by RT-qPCR using specimens from patients.More interestingly,ARHGAP44 mRNA level was lower in tumors with mutant p53 than those with normal p53.Collectively,our results disclose a new mechanism by which mutant p53 stimulates cell spreading and migration.
基金
supported by the National Program on Key Basic Research Project(2015CB901402)
the National Natural Science Foundation of China(91629103,31670882, 81471066,81261120555,81672883,81401837,31071875,31200878, 31100946)
the Science and Technology Commission of Shanghai Municipality(14430712100,11ZR1410000,16ZR1410000,16QA1401500)
the Applied Basic Research Program of Science and Technology Department of Sichuan Province(2015JY0038)
