Identification of the primary growth response gene, ST2/T1, as a gene whose expression is differentially regulated by different protein kinase C isozymes

Abstract

kbstract Individual protein kinase C isozymes have been shown Io play different roles in mediating proliferation, differentiation and transformation, but it is not known to what extent these effects involve induction of expression of particular genes. To explore the differential gene expression that might be induced by activation of different PKC isozymes, we stably transfected NIH 3T3 cells with expression vectors that encode the isozymes PKC-~, -Eli, -V, -~i, -c, -~ and -~l. Using differential display-reverse transcription-polymerase chain reaction we isolated a small eDNA that encodes a portion of the primary response gene, ST2 (also referred to as T1 or DER4), and we confirmed by RNA blot studies that ST2fYI expression is differentially regulated by PKC isozymes. ST2/TI mRNA is undetectable in the unstimulated parental NIH 3T3 cells that express only the a isozyme of PKC, but it can be induced by phorbol ester treatment. Clones that overexpress PKC-a, -5 or -e similarly do not express ST2/TI until they are stimulated with phorbol esters, which induces expression of ST2/TI with kinetics similar to wild-type NIH 3T3 but to different extents. In contrast, ST2/TI mRNA is already present in unstimulated cells that overexpress PKC-~III, -V, -~ and -~l, but phorbol ester greatly enhances ST2frl expression in these cells. These results suggest a differential role for PKC isozymes in mediating the ST2ffl expression that is induced by growth stimuli.

Characteristics of the Novel Interleukin Family Biomarker ST2 in Patients With Acute Heart Failure

“…The ST2 gene is a member of the IL-1 receptor family (1,2); the protein products of ST2 gene, ST2L and soluble ST2, are biomechanically induced in cardiomyocytes (5). The functionally active transmembrane form, ST2L, plays a role in modulating responses of T-helper type 2 cells (6) and is involved in the development of immunologic tolerance (22), but also has a prominent role in ameliorating fibrosis in the context of cardiovascular stretch via binding of IL-33.…”

“…The ST2 gene encodes a protein that is a member of the interleukin (IL)-1 receptor family (1,2) and consists of both a transmembrane receptor form (ST2L) and a truncated, soluble receptor form (ST2) that can be detected in serum (3,4). The ST2 gene is markedly up-regulated in cardiac myocytes and fibroblasts subjected to mechanical strain (5), which is important as the functional ligand of ST2 was identified to be IL-33, a cardiac fibroblast product also induced by mechanical strain (6).…”

Measurement of the Interleukin Family Member ST2 in Patients With Acute Dyspnea

“…The ST2 gene, a member of the interleukin-1 receptor family (1)(2)(3), was recently described to be markedly upregulated in an experimental model of heart failure (HF) (4). The ST2 is thought to bind interleukin-33, another hormone induced and released after stretch of cardiomyocytes (5,6), and interruption of the ST2 gene results in progressive myocardial fibrosis and hypertrophy in experimental models (5).…”

Protein Kinase C Isozymes Differentially Regulate Promoters Containing PEA-3/12-O-Tetradecanoylphorbol-13-acetate Response Element Motifs

“…Kariya et al (1991) have shown that the ␤-myosin heavy chain promoter is regulated better by PKC ␤ than by ␣. In addition, the primary response gene, ST2, has recently been shown to be regulated by PKC ␤II, ␥, , and but not by ␣, ␦, or ⑀ (Kieser et al, 1995), and Hata et al (1993) have shown that a concatenated TRE cluster is trans-activated by PKC ␣, ␤II, and ⑀ but not ␥. Although the results by these investigators are interesting, our data may more accurately reflect PKC isozyme regulation as we have used full-length cellular promoters, transiently expressed PKC isozymes, and physiological stimulation.…”