Publications

The human interleukin-2 receptor alpha (IL2R alpha) gene is transcriptionally activated by both phorbol esters and the HTLV-I trans-activator (Tax) protein through a mechanism that involves the interaction of inducible DNA binding proteins with a kappa B-like enhancer element (-267 to -256). Using mutated IL2R alpha promoter constructs in transient transfection and DNA binding assays, we now demonstrate that sequences located immediately upstream and downstream of the kappa B enhancer also contribute to the regulation of IL2R alpha gene expression. One upstream sequence termed UE-1 is preferentially required for phorbol ester relative to Tax-induced activation and specifically interacts with a constitutively expressed 56-kD cellular factor. In contrast, two overlapping downstream elements between nucleotides -252 and -239 appear to be required for both phorbol ester and Tax-induced activation. One of these elements, an Sp1-like sequence, binds a constitutively expressed 100-kD T-cell protein consistent in size with Sp1 isolated from HeLa cells. The second element, located between the kappa B and Sp1 sites, resembles the decanucleotide core of the serum response element (SRE) from the c-fos gene and interacts with a constitutively expressed factor. Together, these findings implicate a functional role for multiple constitutively expressed DNA binding proteins, in addition to the inducible kappa B-specific factors, in the overall regulation of IL2R alpha gene activation.

Mouse MA-10 Leydig tumor cells synthesize and secrete progesterone in response to human chorionic gonadotropin, luteinizing hormone, and cAMP but may not synthesize androgens. Maximal doses of human chorionic gonadotropin, ovine luteinizing hormone, forskolin, or 8-bromoadenosine 3',5'-cyclic monophosphate, stimulated cytochrome P450scc mRNA accumulation 1.5- to 3-fold and progesterone secretion 10- to 100-fold in MA-10 cells. P450scc mRNA increased by 2 hr and was maximal by 8 hr; polymerase run-on experiments showed this was due to increased P450scc gene transcription. MA-10 cells are a hormonally homogeneous population, as all cells expressed P450scc mRNA and responded to cAMP equally. cAMP-stimulated accumulation of P450scc mRNA continued in the presence of cycloheximide. Gonadotropins stimulated testicular steroidogenesis by coordinate cAMP-induced increases in P450scc gene transcription, mRNA accumulation, and P450scc activity. We cloned rat P450c17 cDNA and showed it detected no P450c17 mRNA in control or cAMP-stimulated MA-10 cells by RNA transfer blots or RNase protection assays. Similarly, HPLC detected no 17 alpha-hydroxyprogesterone or testosterone synthesis in MA-10 cells. Thus MA-10 cells, unlike untransformed Leydig cells, do not express detectable amounts of P450c17 mRNA or P450c17 activity.

Quantitative CT demonstrated increased CSF and 3rd ventricular volumes, and decreased gray matter and white matter volume, in older (greater than 45 years) Down's syndrome (DS) adults with dementia as compared with younger DS adults. Serial CT studies repeated after periods of up to 2 years demonstrated significant progressive cerebral atrophy. Older DS adults without dementia, but with cognitive decline, did not show cerebral atrophy as compared with young DS subjects. These results suggest brain atrophy must be present to accompany dementia in older DS subjects, despite the presence of Alzheimer's disease neuropathology in all older subjects. The Alzheimer's disease process in DS may occur in 2 stages, the 1st with neuropathology and cognitive decline, the 2nd with additional cerebral atrophy and dementia.