| First Author | Ostojić J | Year | 2021 |
| Journal | Cell Rep | Volume | 35 |
| Issue | 7 | Pages | 109136 |
| PubMed ID | 34010639 | Mgi Jnum | J:307116 |
| Mgi Id | MGI:6717054 | Doi | 10.1016/j.celrep.2021.109136 |
| Citation | Ostojic J, et al. (2021) Transcriptional co-activator regulates melanocyte differentiation and oncogenesis by integrating cAMP and MAPK/ERK pathways. Cell Rep 35(7):109136 |
| abstractText | The cyclic AMP pathway promotes melanocyte differentiation by activating CREB and the cAMP-regulated transcription co-activators 1-3 (CRTC1-3). Differentiation is dysregulated in melanomas, although the contributions of CRTC proteins is unclear. We report a selective differentiation impairment in CRTC3 KO melanocytes and melanoma cells, due to downregulation of oculo-cutaneous albinism II (OCA2) and block of melanosome maturation. CRTC3 stimulates OCA2 expression by binding to CREB on a conserved enhancer, a regulatory site for pigmentation and melanoma risk. CRTC3 is uniquely activated by ERK1/2-mediated phosphorylation at Ser391 and by low levels of cAMP. Phosphorylation at Ser391 is constitutively elevated in human melanoma cells with hyperactivated ERK1/2 signaling; knockout of CRTC3 in this setting impairs anchorage-independent growth, migration, and invasiveness, whereas CRTC3 overexpression supports cell survival in response to the mitogen-activated protein kinase (MAPK) inhibitor vemurafenib. As melanomas expressing gain-of-function mutations in CRTC3 are associated with reduced survival, our results suggest that CRTC3 inhibition may provide therapeutic benefit in this setting. |
