Biomedical subjects

Timothy C Hallstrom

Publications and source records attributed to Timothy C Hallstrom.

4 recordsLinked to original sources

PubMed2006

Jab1 is a specificity factor for E2F1-induced apoptosis.

The members of the E2F family of transcription factors are key regulators of genes involved in cell cycle progression, cell fate determination, DNA damage repair, and apoptosis. Many cell-based experiments suggest that E2F1 is a stronger inducer of apoptosis than the other E2Fs. Our previous work identified the E2F1 marked box and flanking region as critical for the specificity in E2F1 apoptosis induction. We have now used a yeast two-hybrid screen to identify proteins that bind the E2F1 marked box and flanking regions, with a potential role in E2F1 apoptosis induction. We identified Jab1 as an E2F1-specific binding protein and showed that Jab1 and E2F1 coexpression synergistically induce apoptosis, coincident with an induction of p53 protein accumulation. In contrast, Jab1 does not synergize with E2F1 to promote cell cycle entry. Cells depleted of Jab1 are deficient for both E2F1-induced apoptosis and induction of p53 accumulation. We suggest that Jab1 is an essential cofactor for the apoptotic function of E2F1.

Adenoviridae↗

PubMed2004

Transcriptional regulation by Lge1p requires a function independent of its role in histone H2B ubiquitination.

Saccharomyces cerevisiae cells that have lost their mitochondrial genome (rho(0)) strongly induce transcription of multidrug resistance genes, including the ATP-binding cassette transporter gene PDR5. PDR5 induction in rho(0) cells requires the presence of the zinc cluster transcription factor Pdr3p. The PDR3 gene is positively autoregulated in rho(0) cells by virtue of the presence of two binding sites for Pdr3p in its promoter. We identify the novel protein Lge1p as a required participant in the rho(0) activation of PDR3 and PDR5 expression. Lge1p is a nuclear protein that has been found to play a role in ubiquitination of histone H2B at Lys(123). This ubiquitination requires the presence of the ubiquitin-conjugating enzyme Rad6p and the ubiquitin ligase Bre1p. Interestingly, rho(0) strains lacking Lge1p failed to induce PDR3 transcription, but induction was still seen in Deltarad6, Deltabre1, and H2B-K123R mutant strains. Microarray experiments also confirmed that the pattern of gene expression changes seen in cells lacking Lge1p, Bre1p, or Rad6p or containing the H2B-K123R mutant as the only form of H2B share some overlap but are distinct. These findings provide a strong argument that Lge1p has roles in gene regulation independent of its participation in the Rad6p-dependent ubiquitination of H2B.

ATP-Binding Cassette Transporters↗

PubMed2003

Specificity in the activation and control of transcription factor E2F-dependent apoptosis.

Previous work has demonstrated a role for the E2F1 gene product in signaling apoptosis, both as a result of the deregulation of the Rb/E2F pathway as well as in response to DNA damage. We now show that the ability of cells to suppress the apoptotic potential of E2F1, as might occur during the course of normal cellular proliferation, requires the action of the Ras-phosphoinositide 3-kinase-Akt signaling pathway. In addition, we also identify a domain within the E2F1 protein, previously termed the marked-box domain, that is essential for the apoptotic activity of E2F1 and that distinguishes the E2F1 protein from E2F3. We also show that the E2F1-marked-box domain is essential for the induction of both p53 and p73 accumulation. Importantly, a role for the marked-box domain in the specificity of E2F1-mediated apoptosis coincides with recent work demonstrating a role for this domain in achieving specificity in the activation of transcription. We conclude that the unique capacity of E2F1 to trigger apoptosis reflects a specificity of transcriptional activation potential, and that this role for E2F1 is regulated through the action of the Akt protein kinase.

Apoptosis↗

PubMed2003

Identification of E-box factor TFE3 as a functional partner for the E2F3 transcription factor.

Various studies have demonstrated a role for E2F proteins in the control of transcription of genes involved in DNA replication, cell cycle progression, and cell fate determination. Although it is clear that the functions of the E2F proteins overlap, there is also evidence for specific roles for individual E2F proteins in the control of apoptosis and cell proliferation. Investigating protein interactions that might provide a mechanistic basis for the specificity of E2F function, we identified the E-box binding factor TFE3 as an E2F3-specific partner. We also show that this interaction is dependent on the marked box domain of E2F3. We provide evidence for a role for TFE3 in the synergistic activation of the p68 subunit gene of DNA polymerase alpha together with E2F3, again dependent on the E2F3 marked box domain. Chromatin immunoprecipitation assays showed that TFE3 and E2F3 were bound to the p68 promoter in vivo and that the interaction of either E2F3 or TFE3 with the promoter was facilitated by the presence of both proteins. In contrast, neither E2F1 nor E2F2 interacted with the p68 promoter under these conditions. We propose that the physical interaction of TFE3 and E2F3 facilitates transcriptional activation of the p68 gene and provides strong evidence for the specificity of E2F function.

3T3 Cells↗