Oncogene-Induced Senescence Does Not Require the p16INK4a or p14ARF Melanoma Tumor Suppressors

Abstract

Oncogene-induced senescence is considered to act as a potent barrier to cell transformation, and has been seen in vivo during the early stages of tumor development. Human nevus cells frequently express oncogenic N-RAS or B-RAF, and are thought to be permanently growth arrested. Many studies have suggested that the p16(INK4a) and, to a lesser extent, the p14ARF tumor suppressor proteins act as critical triggers of oncogene-induced senescence in nevi, and thus these proteins represent major inhibitors of progression to melanoma. There have also been reports, however, showing that p16(INK4a) and/or p14ARF is not sufficient to execute the oncogene-induced senescence program. In this study, we examined the impact of melanoma-associated N-RAS(Q61K) on melanocyte senescence and utilized RNA-interference vectors to directly assess the individual contribution of human p14ARF and p16(INK4a) genes to the N-RAS-induced senescence program. We formally show that cultured human melanocytes can initiate an effective oncogene-mediated senescence program in the absence of INK4a/ARF-encoded proteins. Our data are consistent with observations showing that senescent nevus cells do not always express p16(INK4a), and highlight the need to thoroughly explore INK4a/ARF-independent molecular pathways of senescence in human melanocytes.

Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma

“…Cell authentication was confirmed using the StemElite ID system from Promega. Lentiviruses were produced in HEK293T cells using expression vectors encased in viral capsid encoded by three packaging plasmids as described earlier 59,60 . Cells were infected using a multiplicity of infection of 1-5 to provide an efficiency of infection above 90%.…”

The essence of senescence: Figure 1.

“…Indeed, OIS mechanisms do not seem to be universal across cell types and genetic contexts. This is also exemplified by the signaling routes relaying OIS by RAS V12 versus BRAF E600 : Whereas RAS V12 -induced senescence can be bypassed by abrogation of the p16 INK4A -RB pathway (Serrano et al 1997 (Haferkamp et al 2009). …”

Evidence of oncogene-induced senescence in thyroid carcinogenesis

“…INK4a alone is not sufficient to execute the OIS programme (Michaloglou et al 2005, Haferkamp et al 2009). In our experimental setting the inactivation of p16…”