VRK1 Signaling Pathway in the Context of the Proliferation Phenotype in Head and Neck Squamous Cell Carcinoma

Abstract

The vaccinia-related kinase (VRK) proteins are a new family with three members in the human kinome. The VRK1 protein phosphorylates several transcription factors and has been postulated to be involved in regulation of cell proliferation. In normal squamous epithelium, VRK1 is expressed in the proliferation area. Because VRK1 can stabilize p53, the expression of the VRK1 protein was analyzed in the context of the p53 pathway and the proliferation phenotype in a series of 73 head and neck squamous cell carcinomas. VRK1 protein level positively correlated with p53 response proteins, particularly hdm2 and p21. The VRK1 protein also correlated positively with several proteins associated with proliferation, such as cyclin-dependent kinase 2 (CDK2), CDK6, cdc2, cyclins B1 and A, topoisomerase II, survivin, and Ki67. The level of VRK1 protein behaves like a proliferation marker in this series of head and neck squamous cell carcinomas. To identify a possible regulatory role for VRK1 and because it regulates gene transcription, the promoters of two genes were studied, CDK2 and SURVIVIN, whose proteins correlated positively with VRK1. VRK1 increases the activity of both the CDK2 and SURVIVIN gene promoters. The expression of VRK1 was analyzed in the context of regulators of the G 1 -S transition. VRK1 protein levels increase in response to E2F1 and are reduced by retinoblastoma and p16. These data suggest that VRK1 might play a role in cell cycle regulation and is likely to represent the beginning of a new control mechanism of cell cycle, particularly late in the G 1 -S phase.

Proteomics Identification of Nuclear Ran GTPase as an Inhibitor of Human VRK1 and VRK2 (Vaccinia-related Kinase) Activities

“…The VRK1 protein is very stable and, in continuously growing cells, is always present at relatively high levels (19); because of that it has been associated with cell proliferation (2,5,6). But this kinase, which can regulate several transcription factors, may not always be necessary, and therefore it is likely to be regulated either spatially or temporally.…”

“…Since completion of the human kinome, a new subfamily of serine-threonine kinases, known as vaccinia-related kinases (VRKs), 1 has been identified (1) that is composed of three proteins (2), two of which are catalytically active, VRK1 and VRK2 (3,4), and are mainly expressed in proliferating cells (2,5,6). These proteins have a conserved kinase domain but differ in their regulatory region with little conservation among them or with any other protein.…”

“…Recently VRK1 has been shown to phosphorylate histone H3 in Thr-3 and Ser-10 residues and is implicated in chromatin condensation (18). VRK1 expression has been correlated with several proliferation markers in head and neck squamous cell carcinomas (6). VRK1 expression parallels that of c-myc and c-fos and occurs early in the G 1 phase (19).…”

A genetic view of laryngeal cancer heterogeneity

“…In SCCHN, VRK1 could be a significant control mechanism of the cell cycle, particularly in G1-S phase. 67 Stat3 pathway Stat3 (signal transducer and activator of transcription 3) is a transcription factor that responds to cytokines and growth factor receptor activation. 68 Constitutive activation of the pathway in response to deregulate upstream signals is commonly observed in diverse cancers including dead and neck and laryngeal tumors.…”

Macro Histone H2A1.2 (MacroH2A1) Protein Suppresses Mitotic Kinase VRK1 during Interphase

“…VRK1 can also phosphorylate activating transcription factor 2 and c-Jun by its interaction with JNK (7,8). During cell cycle progression, VRK1 has been shown to phosphorylate barrier-to-autointegration factor (BAF), 2 which is believed to compact DNA (9 -11), and it has also been shown to be involved in promoting the transcription of proliferation-related proteins such as retinoblastoma, cyclin-dependent kinase-2, and survivin (12). Additionally, VRK1 can increase cyclin D1 expression via the phosphorylation of the cAMP-response elementbinding protein and has a major role in the G 1 /S transition (13,14).…”