title: p53-related protein kinase confers poor prognosis and represents a novel therapeutic target in multiple myeloma.
abstract: p53-related protein kinase (TP53RK, also known as PRPK) is an upstream kinase that phosphorylates (serine residue Ser15) and mediates p53 activity. Here we show that TP53RK confers poor prognosis in multiple myeloma (MM) patients, and, conversely, that TP53RK knockdown inhibits p53 phosphorylation and triggers MM cell apoptosis, associated with downregulation of c-Myc and E2F-1-mediated upregulation of pro-apoptotic Bim. We further demonstrate that TP53RK downregulation also triggers growth inhibition in p53-deficient and p53-mutant MM cell lines and identify novel downstream targets of TP53RK including ribonucleotide reductase-1, telomerase reverse transcriptase, and cyclin-dependent kinase inhibitor 2C. Our previous studies showed that immunomodulatory drugs (IMiDs) downregulate p21 and trigger apoptosis in wild-type-p53 MM.1S cells, Importantly, we demonstrate by pull-down, nuclear magnetic resonance spectroscopy, differential scanning fluorimetry, and isothermal titration calorimetry that IMiDs bind and inhibit TP53RK, with biologic sequelae similar to TP53RK knockdown. Our studies therefore demonstrate that either genetic or pharmacological inhibition of TP53RK triggers MM cell apoptosis via both p53-Myc axis-dependent and axis-independent pathways, validating TP53RK as a novel therapeutic target in patients with poor-prognosis MM.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cottini
authors.affiliation: Discovery and Preclinical Research Division, TAIHO Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nozawa
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
authors.forename: Hyuk-Soo
authors.initials: HS
authors.lastname: Seo
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Ohguchi
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; and.|Harvard School of Public Health, Boston, MA.
authors.forename: Mehmet K
authors.initials: MK
authors.lastname: Samur
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Diana
authors.initials: D
authors.lastname: Cirstea
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Naoya
authors.initials: N
authors.lastname: Mimura
authors.affiliation: Discovery and Preclinical Research Division, TAIHO Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Iwasawa
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Walter
authors.initials: W
authors.lastname: Massefski
authors.affiliation: Discovery and Preclinical Research Division, TAIHO Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Teruhiro
authors.initials: T
authors.lastname: Utsugi
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
authors.forename: Sirano
authors.initials: S
authors.lastname: Dhe-Paganon
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D055785:Gene Knockdown Techniques; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009101:Multiple Myeloma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*
chemical_list: D007155:Immunologic Factors; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C441644:TP53RK protein, human