ABSTRACT
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.
Subject(s)
Carcinoma, Squamous Cell/metabolism , DNA, Neoplasm/metabolism , DNA-Binding Proteins/physiology , Gene Expression Regulation, Neoplastic/physiology , Nuclear Proteins/physiology , Phosphoproteins/metabolism , Proto-Oncogene Proteins c-mdm2/metabolism , Skin Neoplasms/metabolism , Trans-Activators/metabolism , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Proteins/physiology , Animals , Animals, Newborn , Carcinoma, Squamous Cell/genetics , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Mice , Mice, Inbred BALB C , Nuclear Proteins/biosynthesis , Nuclear Proteins/genetics , Phosphoproteins/antagonists & inhibitors , Protein Binding/physiology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Repressor Proteins/antagonists & inhibitors , Repressor Proteins/physiology , Skin Neoplasms/genetics , Trans-Activators/antagonists & inhibitors , Tumor Protein p73 , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Proteins/biosynthesis , Tumor Suppressor Proteins/geneticsABSTRACT
Electrochemical studies of sodium and its salts were carried out in 0.1 M TBAP and in electrolyte-free tetrahydrofuran solutions at room temperature. Working electrodes employed in these studies were platinum and mercury film ultramicroelectrodes, as well as a sodium electrode. The electrochemical reduction of sodium salts in 0.1 M TBAP/THF solutions leads to deposition of sodium on the platinum surface, and at more negative potentials, a stripping wave attributed to formation of the sodium anion is observed; the oxidation wave for the sodium anion is not observed. Possible mechanisms for the removal of the anion by competing processes are discussed. The results obtained from electrochemical studies of sodium electrodes and of sodium salts at a mercury film electrode are presented.
ABSTRACT
Premedical advisors can carry out many varied activities, but all require commitment, resources, and personal interest. Premedical and health career advising appear to be most successful when the task is not assigned to one individual, but is assumed as a university responsibility. Also, premedical advisors seem to be valued more and to have fewer conflicts when they are known by health professional schools and work together with them. Medical schools have a responsibility to assist and support premedical advisors more than is done at present. This need will become increasingly important if the high quality of applicants to medical school is to be maintained in an apparently shrinking applicant pool.(1)
