Publications

The p53 family consists of three transcription factors, p53, p63 and p73 that share domain architecture and sequence identity. The mTOR (mammalian target of rapamycin) kinase responds to growth factors and nutrient levels to regulate cellular growth and autophagy. Whereas p53 acts both upstream and downstream of mTOR, gene signature-based analyses have revealed that p73 is inhibited by mTOR activity. p53 can both activate and repress autophagy levels depending on cellular context. While less is known about p73, recent studies have shown that it induces cellular autophagy and multiple autophagy-associated genes downstream of mTOR. Chromatin immunoprecipitation analyses demonstrate that endogenous p73 binds the regulatory regions of genes such as ATG5, ATG7 and UVRAG. How p73 regulates the expression levels of these genes in response to different cellular stresses remains unknown. Because p53 family members play key roles in tumor suppression, development, aging and neurodegeneration, the context and manner by which these transcription factors regulate autophagy may have implications for a wide range of human diseases.

Antigen receptor signaling in lymphocytes has been clearly implicated in the pathogenesis of the rheumatic diseases. Here, we review evidence from mouse models in which B-cell and T-cell signaling machinery is perturbed as well as data from functional studies of primary human lymphocytes and recent advances in human genetics. B-cell receptor hyper-responsiveness is identified as a nearly universal characteristic of systemic lupus erythematosus in mice and humans. Impaired and enhanced T-cell receptor signaling are both associated with distinct inflammatory diseases in mice. Mechanisms by which these pathways contribute to disease in mouse models and patients are under active investigation.

Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8 x 10(-5)), establishing a novel phenotype for this genetic variant.

Histone deacetylase (HDAC) inhibitors are a novel class of anti-tumor agents with a potential role in the treatment of breast cancer. In ER-positive cells, treatment with selective and non-selective HDAC inhibitors has been associated with a transcriptional down-regulation (and possibly protein modification via the HSP90 chaperone function) of ER and its response genes. In ER-negative cell lines, HDAC inhibitors have been shown to re-establish ER expression. In addition, HDAC inhibitors have been reported to modulate the progesterone receptor. Despite the opposing effects in ER-positive and ER-negative breast cancer cells, the addition of an HDAC inhibitor potentiated and restored the efficacy of anti-estrogen therapy in preclinical models. This has led to the initiation of several clinical trials combining HDAC inhibitors with anti-estrogen therapy. In this review, we will summarize the relationship between estrogen signaling and HDACs, examine how HDAC inhibitors impact this relationship and synergize with anti-estrogens to inhibit tumor growth, and discuss the clinical possibilities and potential of this new approach.