| RRC ID |
73271
|
| 著者 |
Ohe S, Kubota Y, Yamaguchi K, Takagi Y, Nashimoto J, Kozuka-Hata H, Oyama M, Furukawa Y, Takekawa M.
|
| タイトル |
ERK-mediated NELF-A phosphorylation promotes transcription elongation of immediate-early genes by releasing promoter-proximal pausing of RNA polymerase II.
|
| ジャーナル |
Nat Commun
|
| Abstract |
Growth factor-induced, ERK-mediated induction of immediate-early genes (IEGs) is crucial for cell growth and tumorigenesis. Although IEG expression is mainly regulated at the level of transcription elongation by RNA polymerase-II (Pol-II) promoter-proximal pausing and its release, the role of ERK in this process remains unknown. Here, we identified negative elongation factor (NELF)-A as an ERK substrate. Upon growth factor stimulation, ERK phosphorylates NELF-A, which dissociates NELF from paused Pol-II at the promoter-proximal regions of IEGs, allowing Pol-II to resume elongation and produce full-length transcripts. Furthermore, we found that in cancer cells, PP2A efficiently dephosphorylates NELF-A, thereby preventing aberrant IEG expression induced by ERK-activating oncogenes. However, when PP2A inhibitor proteins are overexpressed, as is frequently observed in cancers, decreased PP2A activity combined with oncogene-mediated ERK activation conspire to induce NELF-A phosphorylation and IEG upregulation, resulting in tumor progression. Our data delineate previously unexplored roles of ERK and PP2A inhibitor proteins in carcinogenesis.
|
| 巻・号 |
13(1)
|
| ページ |
7476
|
| 公開日 |
2022-12-3
|
| DOI |
10.1038/s41467-022-35230-4
|
| PII |
10.1038/s41467-022-35230-4
|
| PMID |
36463234
|
| PMC |
PMC9719515
|
| MeSH |
Carcinogenesis
Genes, Immediate-Early*
Humans
Phosphorylation
RNA Polymerase II* / genetics
Transcription Factors
|
| IF |
12.121
|
| リソース情報 |
| ヒト・動物細胞 |
293(RCB1637)
COS-7(RCB0539)
HeLa(RCB0007)
A549(RCB3677)
A431(RCB0202)
293gp(RCB2354) |
