VRK1 signaling pathway in the context of the proliferation phenotype in head and neck squamous cell carcinoma.
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 G1-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 G1-S phase.
Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Cientificas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
Claudio R
CR
Santos
María
M
Rodríguez-Pinilla
Francisco M
FM
Vega
José L
JL
Rodríguez-Peralto
Sandra
S
Blanco
Ana
A
Sevilla
Alberto
A
Valbuena
Teresa
T
Hernández
André J
AJ
van Wijnen
Fengzhi
F
Li
Enrique
E
de Alava
Montserrat
M
Sánchez-Céspedes
Pedro A
PA
Lazo
D014408:Biomarkers, Tumor / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000032:analysis / Q000378:metabolism*; D015398:Signal Transduction; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; C109890:VRK1 protein, human; D051357:Cyclin-Dependent Kinase 2