Human p14(ARF)-mediated cell cycle arrest strictly depends on intact p53 signaling pathways.
The tumor suppressor ARF is transcribed from the INK4a/ARF locus in partly overlapping reading frames with the CDK inhibitor p16(Ink4a). ARF is able to antagonize the MDM2-mediated ubiquitination and degradation of p53, leading to either cell cycle arrest or apoptosis, depending on the cellular context. However, recent data point to additional p53-independent functions of mouse p19(ARF). Little is known about the dependency of human p14(ARF) function on p53 and its downstream genes. Therefore, we analysed the mechanism of p14(ARF)-induced cell cycle arrest in several human cell types. Wild-type HCT116 colon carcinoma cells (p53(+/+)p21(CIP1+/+) 14-3-3sigma(+/+)), but not p53(-/-) counterparts, underwent G(1) and G(2) cell cycle arrest following infection with a p14(ARF)-adenovirus. In p21(CIP1-/-) cells, p14(ARF) did not induce G(1) or G(2) arrest, while 14-3-3sigma(-/-) counterparts were mainly arrested in G(1), pointing to essential roles of p21(CIP1) in G(1) and G(2) arrest and cooperative roles of p21 and 14-3-3sigma in ARF-mediated G(2) arrest. Our data demonstrate a strict p53 and p21(CIP1) dependency of p14(ARF)-induced cell cycle arrest in human cells.
Weber
H Oliver
HO
Laboratory of Molecular Tumor Biology, Department of Dermatology, University of Erlangen-Nuremberg, 91052 Erlangen, Germany.
Samuel
Temesgen
T
Rauch
Pia
P
Funk
Jens Oliver
JO
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004440:Ecdysone / Q000494:pharmacology; D005092:Exonucleases; D005095:Exoribonucleases; D016193:G1 Phase; D016195:G2 Phase; D005786:Gene Expression Regulation / Q000187:drug effects; D018390:Gene Targeting; D016158:Genes, p53; D006801:Humans; D007668:Kidney; D009363:Neoplasm Proteins; D011506:Proteins / Q000235:genetics; D011987:Receptors, Steroid / Q000187:drug effects / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013045:Species Specificity; D014162:Transfection; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C055469:ecdysone receptor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004440:Ecdysone; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human