eIF5A-Independent Role of DHPS in p21CIP1 and Cell Fate Regulation. Int J Mol Sci 2021 Dec 07;22(24)
Date
12/25/2021Pubmed ID
34947982Pubmed Central ID
PMC8707118DOI
10.3390/ijms222413187Scopus ID
2-s2.0-85120635476 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
Deoxyhypusine synthase (DHPS) catalyzes the first step of hypusination of the elongation translation factor 5A (eIF5A), and these two proteins have an exclusive enzyme-substrate relationship. Here we demonstrate that DHPS has a role independent of eIF5A hypusination in A375 and SK-MEL-28 human melanoma cells, in which the extracellular signal regulated kinase 1/2 (ERK1/2) pathway is deregulated. We found that RNA interference of DHPS induces G0/G1 cell cycle arrest in association with increased p21CIP1 expression in these cells whereas eIF5A knockdown induces cell death without increasing p21CIP1 expression. Interestingly, p21CIP1 knockdown switched DHPS knockdown-induced growth arrest to cell death in these cells, suggesting a specific relation between DHPS and p21CIP1 in determining cell fate. Surprisingly, ectopic expression of DHPS-K329R mutant that cannot hypusinate eIF5A abrogated DHPS knockdown-induced p21CIP1 expression in these cells, suggesting a non-canonical role of DHPS underlying the contrasting effects of DHPS and eIF5A knockdowns. We also show that DHPS knockdown induces p21CIP1 expression in these cells by increasing CDKN1A transcription through TP53 and SP1 in an ERK1/2-dependent manner. These data suggest that DHPS has a role independent of its ability to hypusinate eIF5A in cells, which appears to be important for regulating p21CIP1 expression and cell fate.
Author List
Becker AE, Wu PK, Park JIAuthor
Jong-In Park PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ApoptosisCell Cycle Checkpoints
Cell Line, Tumor
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p21
Gene Expression Regulation, Neoplastic
Gene Knockout Techniques
HEK293 Cells
Humans
MAP Kinase Signaling System
Mutation
Neoplasms
Oxidoreductases Acting on CH-NH Group Donors
Peptide Initiation Factors
RNA Interference
RNA-Binding Proteins