Disrupting the interaction between a p53 gain-of-function mutant and the transcriptional co-activator PC4 reverses drug resistance in cancer cells

被引：0

作者：

Mondal, Priya ^{[1
]}

Roy, Kumar Singha ^{[2
]}

Bhagat, Supriya Varsha ^{[3
]}

Singh, Siddharth ^{[3
]}

Chattopadhyay, Anupa ^{[4
]}

Ghosh, Damayanti Das ^{[4
]}

Kundu, Tapas K. ^{[3
]}

Roychoudhury, Susanta ^{[2
]}

Roy, Siddhartha ^{[1
]}

机构：

[1] Bose Inst, Dept Biophys, P-1-12 CIT Rd,Scheme 7 M, Kolkata 700054, India

[2] CSIR Indian Inst Chem Biol, Canc Biol & Inflammatory Disorder Div, Kolkata, India

[3] Jawaharlal Nehru Ctr Adv Sci Res, Mol Biol & Genet Unit, Transcript & Dis Lab, Bangalore, India

[4] Saroj Gupta Canc Ctr & Res Inst, Kolkata, India

来源：

FEBS LETTERS | 2024年 / 598卷 / 12期

关键词：

drug resistance; gain-of-function; p53; peptide; protein-protein interaction; HUMAN MDR1; WILD-TYPE; ACTIVATION; GENE;

D O I：

10.1002/1873-3468.14890

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

PC4 is a chromatin-associated protein and transcriptional coactivator whose role in gene regulation by wild-type p53 is now well known. Little is known about the roles of PC4 in tumor cells bearing mutant p53 genes. We show that PC4 associates with one of the tumor-associated gain-of-function p53 mutants, R273H. This association drives its recruitment to two promoters, UBE2C and MDR1, known to be responsible for imparting aggressive growth and resistance to many drugs. Here, we introduced a peptide that disrupts the PC4-R273Hp53 interaction to tumor cells bearing the R273HTP53 gene, which led to a lowering of MDR1 expression and abrogation of drug resistance in a mutant-specific manner. The results suggest that the PC4-R273Hp53 interaction may be a promising target for reducing proliferation and drug resistance in tumors.

引用

页码：1532 / 1542

页数：11

共 20 条

[1] DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53 [J].

Alam, S. K. ;

Yadav, V. K. ;

Bajaj, S. ;

Datta, A. ;

Dutta, S. K. ;

Bhattacharyya, M. ;

Bhattacharya, S. ;

Debnath, S. ;

Roy, S. ;

Boardman, L. A. ;

Smyrk, T. C. ;

Molina, J. R. ;

Chakrabarti, S. ;

Chowdhury, S. ;

Mukhopadhyay, D. ;

Roychoudhury, S. .

CELL DEATH AND DIFFERENTIATION, 2016, 23 (04) :707-722

[2] Post-translational modifications and activation of p53 by genotoxic stresses [J].

Appella, E ;

Anderson, CW .

EUROPEAN JOURNAL OF BIOCHEMISTRY, 2001, 268 (10) :2764-2772

[3] E2 Ubiquitin-conjugating Enzyme, UBE2C Gene, Is Reciprocally Regulated by Wild-type and Gain-of-Function Mutant p53 [J].

Bajaj, Swati ;

Alam, Sk. Kayum ;

Roy, Kumar Singha ;

Datta, Arindam ;

Nath, Somsubhra ;

Roychoudhury, Susanta .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2016, 291 (27) :14231-14247

[4] Activation of p53 function by human transcriptional coactivator PC4: Role of protein-protein interaction, DNA bending, and Posttranslational modifications [J].

Batta, Kiran ;

Kundu, Tapas K. .

MOLECULAR AND CELLULAR BIOLOGY, 2007, 27 (21) :7603-7614

[5] Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy [J].

Blandino, G ;

Levine, AJ ;

Oren, M .

ONCOGENE, 1999, 18 (02) :477-485

[6] p53 gain-of-function mutations increase Cdc7-dependent replication initiation [J].

Datta, Arindam ;

Ghatak, Dishari ;

Das, Sumit ;

Banerjee, Taraswi ;

Paul, Anindita ;

Butti, Ramesh ;

Gorain, Mahadeo ;

Ghuwalewala, Sangeeta ;

Roychowdhury, Anirban ;

Alam, Sk Kayum ;

Das, Pijush ;

Chatterjee, Raghunath ;

Dasgupta, Maitrayee ;

Panda, Chinmay Kumar ;

Kundu, Gopal C. ;

Roychoudhury, Susanta .

EMBO REPORTS, 2017, 18 (11) :2030-2050

[7] Peptide-Protein Interactions Suggest That Acetylation of Lysines 381 and 382 of p53 Is Important for Positive Coactivator 4-p53 Interaction [J].

Debnath, Subrata ;

Chatterjee, Snehajyoti ;

Arif, Mohammed ;

Kundu, Tapas K. ;

Roy, Siddhartha .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (28) :25076-25087

[8] Structural and Drug Targeting Insights on Mutant p53 [J].

Gomes, Ana Sara ;

Ramos, Helena ;

Inga, Alberto ;

Sousa, Emilia ;

Saraiva, Lucilia .

CANCERS, 2021, 13 (13)

[9] Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis [J].

Hanel, W. ;

Marchenko, N. ;

Xu, S. ;

Yu, S. Xiaofeng ;

Weng, W. ;

Moll, U. .

CELL DEATH AND DIFFERENTIATION, 2013, 20 (07) :898-909

[10] Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis [J].

Hiraki, Masatsugu ;

Hwang, So-Young ;

Cao, Shugeng ;

Ramadhar, Timothy R. ;

Byun, Sanguine ;

Yoon, Kyoung Wan ;

Lee, Jung Hyun ;

Chu, Kiki ;

Gurkar, Aditi U. ;

Kolev, Vihren ;

Zhang, Jianming ;

Namba, Takushi ;

Murphy, Maureen E. ;

Newman, David J. ;

Mandinova, Anna ;

Clardy, Jon ;

Lee, Sam W. .

CHEMISTRY & BIOLOGY, 2015, 22 (09) :1206-1216

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