Faculty Collaboration Database

eIF5A-Independent Role of DHPS in p21^CIP1 and Cell Fate Regulation. Int J Mol Sci 2021 Dec 07;22(24)

Date

12/25/2021

Pubmed ID

34947982

Pubmed Central ID

PMC8707118

DOI

10.3390/ijms222413187

Scopus ID

2-s2.0-85120635476 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

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 p21^CIP1 expression in these cells whereas eIF5A knockdown induces cell death without increasing p21^CIP1 expression. Interestingly, p21^CIP1 knockdown switched DHPS knockdown-induced growth arrest to cell death in these cells, suggesting a specific relation between DHPS and p21^CIP1 in determining cell fate. Surprisingly, ectopic expression of DHPS-K329R mutant that cannot hypusinate eIF5A abrogated DHPS knockdown-induced p21^CIP1 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 p21^CIP1 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 p21^CIP1 expression and cell fate.

Author List

Becker AE, Wu PK, Park JI

Author

Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Apoptosis
Cell 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