p73 expression modulates p63 and Mdm2 protein presence in complex with p53 family-specific DNA target sequence in squamous cell carcinogenesis.
The expression of p73 and p63 isoforms is frequently deregulated in human epithelial tumors. We previously showed that loss of p73 protein expression associates with malignant conversion in vivo and ionizing radiation (IR) resistance in vitro in a clonal model of mouse epidermal carcinogenesis. Here we show that loss of endogenous p73 expression in squamous cell carcinoma (SCC) cells and tumors was concomitant with preferential DNA binding of the inhibitory DeltaNp63alpha isoform and reduction of transcriptionally active p63gamma isoforms binding to a p21 promoter sequence in vitro. Reconstitution of TAp73alpha in malignant cells increased the steady state DNA-binding capabilities of the endogenous transcriptionally active TAp63gamma and DeltaNp63gamma isoforms, correlating with restoration of tumor suppression but not IR sensitivity. Loss of p73 in malignant cells also coincided with increased presence of p53 family inhibitor Mdm2 in p53-specific DNA-bound complexes, whereas reconstitution of TAp73alpha expression resulted in exclusion of Mdm2 from these complexes. These results suggest a dual mechanism for TAp73alpha to foster tumor suppression through enhancement of the DNA-binding activity of p63gamma isoforms, and through inhibition of transcriptional repressors Mdm2 or DeltaNp63alpha.
Johnson
J
J
Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA.
Lagowski
J
J
Lawson
S
S
Liu
Y
Y
Kulesz-Martin
M
M
D000818:Animals; D000831:Animals, Newborn; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; C000606460:TP73 protein, human; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2