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Serum response factor (SRF) is a key regulator of a number of extracellular signal-regulated genes important for cell growth and differentiation. A form of the SRF gene with a double mutation (dmSRF) was generated. This mutation reduced the binding activity of SRF protein to the serum response element and reduced the capability of SRF to activate the atrial natriuretic factor promoter that contains the serum response element. Cardiac-specific overexpression of dmSRF attenuated the total SRF binding activity and resulted in remarkable morphologic changes in the heart of the transgenic mice. These mice had dilated atrial and ventricular chambers, and their ventricular wall thicknesses were only ½ to 13the thickness of that of nontransgenic mice. Also these mice had smaller cardiac myocytes and had less myofibrils in their myocytes relative to nontransgenic mice. Altered gene expression and slight interstitial fibrosis were observed in the myocardium of the transgenic mice. All the transgenic mice died within the first 12 days after birth, because of the early onset of severe, dilated cardiomyopathy. These results indicate that dmSRF overexpression in the heart apparently alters cardiac gene expression and blocks normal postnatal cardiac growth and development.

Induction of the Epstein–Barr virus lytic cycle in latently infected B cells requires the expression of the immediate-early lytic gene BZLF1. We have previously identified severalcis-elements within the BZLF1 promoter that are required for induction by known inducers of the lytic cycle [E. Flemington and S.H. Speck (1990)J. Virol.64, 1217–1226]. These include four elements termed the ZI domains (ZIA, ZIB, ZIC, and ZID) that share extensive homology and that have recently been shown to bind several cellular transcription factors [A. M. Borras, J.L. Strominger, and S.H. Speck (1996)J. Virol.70, 3894–3901]. Here Sp1 and Sp3 are identified as the cellular factors present in crude B cell nuclear extract preparations that bind to the ZIC domain. In addition, three of the four complexes observed in electrophoretic mobility shift analyses employing probes containing either the ZIA or the ZID domains also represent Sp1 or Sp3 binding. Binding of Sp1 and Sp3 to the ZI domains was shown to be significantly weaker than binding of these factors to a consensus Sp1 site. A heterologous promoter construct containing three repeats of a consensus Sp1 site, cloned upstream of a single copy of the ZII (CREB/AP1) element from the BZLF1 promoter linked to the β-globin TATA box, exhibited phorbol ester inducibility. The latter observation was consistent with the functional behavior exhibited by a heterologous promoter construct containing multiple copies of the ZIC domain liked to the ZII element. However, the basal activity of the heterologous promoter construct driven by the consensus Sp1 sites was ca. 10-fold higher than that of the heterologous reporter construct containing multimerized ZIC sites. Thus, the low affinity of Sp1 binding to the ZI domains may contribute to the low-level basal activity of the BZLF1 promoter.