Massive Apoptosis of Thymocytes in T-Cell-Deficient Id1 Transgenic Mice

Abstract

Id1 is an inhibitor of a group of basic helix-loop-helix transcription factors, collectively called E proteins, which includes E12, E47, E2-2, and HEB. We have generated transgenic mice in which Id1 is specifically expressed in T cells. The total number of thymocytes in these mice is less than 4% of that in wild-type mice. The majority of the transgenic thymocytes are CD4 and CD8 double negative and bear the cell surface markers of multipotent progenitor cells. A small number of thymocytes, however, differentiate into CD4 or CD8 single-positive T cells, which also display different characteristics from their wild-type counterparts. More importantly, apoptotic cells constitute about 50% of the total thymocytes. These apoptotic thymocytes have rearranged their T-cell receptor genes, suggesting that they are differentiating T cells. This finding has raised the possibility that the T-cell deficiency in Id1 transgenic mice is the result of a massive apoptosis of differentiating T cells triggered by Id1 expression as opposed to a developmental block at the earliest progenitor stage. The progenitor cells accumulated in the transgenic mice might have survived because they are not susceptible to the apoptotic signals. Despite the massive cell death of the thymocytes at young ages, Id1 transgenic mice frequently develop T-cell lymphoma later in their life span, and lymphomagenesis appears to occur at different stages of T-cell development. Taken together, our data suggest that E proteins, being the targets of Id1, are essential regulators for normal T-cell differentiation and tumor suppression.

Human T-Cell Leukemia Virus Type 1 Tax Protein Down-Regulates Pre-T-Cell Receptor Alpha Gene Transcription in Human Immature Thymocytes

“…Furthermore, they are endowed with a potential tumor-suppressing activity, as inactivation of E2A transcriptional activity is an essential and common step toward the development of T-cell malignancies. Thus, in mice, disruption of the E2A gene or inhibition of E2A proteins by Id proteins leads to abnormalities in the earliest stages of ␣␤ T-cell development and to varying degrees of reduced thymic cellularity (1,11,22,23). Later in life, these E2A-deficient mice become prone to developing highly malignant T-cell lymphomas, most of them expressing either CD4 or CD8.…”

Overexpression of Id-1 is significantly associated with tumour angiogenesis in human pancreas cancers

“…It appears that Id-1 protein may be an important new target molecule for antiangiogenic drug design in cancer treatment. Several investigations have demonstrated that Id protein affects cell growth via the mechanisms of cell proliferation and/or apoptosis (Kim et al, 1999;Lin et al, 1999;Norton, 2000;Alani et al, 2001). It has been suggested that Id-1 and Id-2 proteins may function in the bHLH-mediated inactivation of the cyclindependent kinase inhibitors, for example, p21 WAF1 , p16 INK4a and p27 KIP1 (Prabhu et al, 1997;Polsky et al, 2001;Ouyang et al, 2002b;Singh et al, 2002).…”

Id and development

“…Overexpression studies of Id proteins in several in vivo systems have also been carried out (Sun, 1994;Martinsen and Bronner-Fraser, 1998;Wice and Gordon, 1998;Morrow et al, 1999;Kim et al, 1999;Cai et al, 2000). Phenotypes detected in both gain-of-function and loss-of-function experiments give us insight into potential bHLH proteins as well as regulatory roles of Id proteins in the respective organ development.…”