GRWD1 explained

Glutamate-rich WD repeat-containing protein 1 is a WD40 repeat protein (containing five WD40 repeat motifs) that in humans is encoded by the GRWD1 gene. It localizes to the nucleus and has known functions in regulating chromatin accessibilty and loading of the MCM helicase.^{[1] [2]} GRWD1 has also been shown to play a critical role in ribosome biogenesis.

Role in cancer

While some ribosomal proteins like RPL5 and RPL11 are suggested to act as tumor suppressors by inhibiting E3 ubiquitin-protein ligase MDM2 and thus activating p53, others, such as GRWD1, may promote tumorigenesis. Overexpression of GRWD1 suppresses p53 and transforms normal cells, possibly through its interaction with RPL11, preventing it from regulating MDM2.^[3]

In addition to its interaction with RPL11, GRWD1 directly interacts with wild-type p53, suppressing its transcriptional activity.^[4] Furthermore, overexpression of GRWD1 has been linked to the activation of oncogenic signaling pathways, such as the Notch signaling pathway, through the upregulation of ADAM17.^[5]

Further reading

• Nagase T, Kikuno R, Ohara O . Prediction of the coding sequences of unidentified human genes. XXII. The complete sequences of 50 new cDNA clones which code for large proteins . DNA Research . 8 . 6 . 319–327 . December 2001 . 11853319 . 10.1093/dnares/8.6.319 .
• Scherl A, Couté Y, Déon C, Callé A, Kindbeiter K, Sanchez JC, Greco A, Hochstrasser D, Diaz JJ . Functional proteomic analysis of human nucleolus . Molecular Biology of the Cell . 13 . 11 . 4100–4109 . November 2002 . 12429849 . 133617 . 10.1091/mbc.E02-05-0271 .
• Trzcińska AM, Girstun A, Piekiełko A, Kowalska-Loth B, Staroń K . Potential protein partners for the N-terminal domain of human topoisomerase I revealed by phage display . Molecular Biology Reports . 29 . 4 . 347–352 . December 2002 . 12549820 . 10.1023/A:1021237021338 . 9602116 .
• Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G . A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway . Nature Cell Biology . 6 . 2 . 97–105 . February 2004 . 14743216 . 10.1038/ncb1086 . 11683986 .
• Andersen JS, Lam YW, Leung AK, Ong SE, Lyon CE, Lamond AI, Mann M . Nucleolar proteome dynamics . Nature . 433 . 7021 . 77–83 . January 2005 . 15635413 . 10.1038/nature03207 . 4344740 . 2005Natur.433...77A .
• Higa LA, Wu M, Ye T, Kobayashi R, Sun H, Zhang H . CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation . Nature Cell Biology . 8 . 11 . 1277–1283 . November 2006 . 17041588 . 10.1038/ncb1490 . free . 22180568 . 10397/34293 .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–648 . November 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .

Notes and References

1. Gratenstein K, Heggestad AD, Fortun J, Notterpek L, Pestov DG, Fletcher BS . The WD-repeat protein GRWD1: potential roles in myeloid differentiation and ribosome biogenesis . Genomics . 85 . 6 . 762–773 . June 2005 . 15885502 . 10.1016/j.ygeno.2005.02.010 .
2. Web site: Entrez Gene: GRWD1 glutamate-rich WD repeat containing 1.
3. Takafuji T, Kayama K, Sugimoto N, Fujita M . GRWD1, a new player among oncogenesis-related ribosomal/nucleolar proteins . Cell Cycle . 16 . 15 . 1397–1403 . August 2017 . 28722511 . 5553401 . 10.1080/15384101.2017.1338987 .
4. Ichikawa MK, Saitoh M . Direct and indirect roles of GRWD1 in the inactivation of p53 in cancer . Journal of Biochemistry . 171 . 6 . 601–603 . May 2022 . 35171268 . 10.1093/jb/mvac010 .
5. Ding H, Feng Z, Hu K . GRWD1 Over-Expression Promotes Gastric Cancer Progression by Activating Notch Signaling Pathway via Up-Regulation of ADAM17 . Digestive Diseases and Sciences . 69 . 3 . 821–834 . March 2024 . 38172445 . 10.1007/s10620-023-08208-5 .