Prof. Don's Lab
Prof. Jeremy (Ramy) Don is a Senior Lecturer at the Mina and Everard Goodman Faculty of Life Sciences at Bar-Ilan University. With his research team, he is investigating the intricacies of cell and human reproduction, as applied to both developmental biology and how this factors into the development and growth of certain types of cancer.
Cure for Cancer Research
Don’s lab studies molecular factors involved in cancer onset. About ten years ago, they identified a gene implicated in human lymphoma, the PIM2 gene—a serine/threonine kinase, now known for its cancer-causing activity, with an anti-apoptotic function—discovering significant elevation in its level during different human lymphomas and making a direct correlation between its level and the severity of the disease.
More recently Don’s team demonstrated that although, this lymphoma-related gene may function as a potent survival factor (an oncogenic role), under different circumstances it may exhibit pro-apoptotic properties (anti-oncogenic role).
The laboratory discoveries of Don’s team, which highlighted the radically different behaviors of the PIM2 gene, require further in depth study of the gene’s molecular pathways. The differential effects of PIM2 underscore that while targeting PIM2’s kinase activity, some cancers will benefit from a chemotherapeutic treatment, but other cancers may not react to these treatments in an expected course.
Understanding the Molecular Program of Spermatogenesis: MEIG1
Cloning and isolating mouse genes have allowed Don’s team unique insights into the process of spermatogenesis. MEIG1 was first identified and cloned as a meiosis-specific gene (meiosis is a very fundamental process in gamete production in which the genome is reduced by half).
It became apparent that a nuclear form of MEIG1 appears in meiotic spermatocytes where it physically attaches to the meiotic chromosomes, forming foci-like structures along them. A biochemical study suggested that nuclear localization of the MEIG1 protein depends on phosphorylation of specific tyrosine residues.
MEIG1 is a highly conserved protein, affirming its importance during evolution. The team hypothesized that MEIG1 might function in processes responsible for DNA integrity, and in research cases where MEIG1 was deleted from the genome of male mice, they were rendered completely unable to produce mature sperm cells; those few sperm cells that did reach the epididymis had fragmented DNA.
Don’s research team also found that proteins extracted from cells without MEIG1 are less efficient in rejoining DNA ends, as compared to wild-type cells, and that MEIG1 appears in the nucleus of differentiating lymphocytes undergoing processes of DNA rearrangement. Additionally, these mice without MEIG1 were found more susceptible for developing tumors over the time, allowing the theory that MEIG1 may be a factor not only in fertility problems but also in immunological failure and development of cancer.
Understanding the Molecular Program of Spermatogenesis: ATCE1
Two key questions in the cycle of sexual reproduction involve timing and signals. What prevents the egg from starting haploid embryonic development? If the egg is waiting for molecular signals transmitted by the sperm, what are these egg-activating sperm factors? Some have been identified, but none are a transcription factor.
ATCE1 anchored to the acrosome membrane
In the laboratory, Don’s research team isolated the gene ATCE1. It encodes a potent transcription factor which structurally belongs to a specific family of transcription factors, the CREB/ATF family. Unlike all other members of this family of transcription factors, ATCE1 uses a different DNA motif to activate transcription.
The ATCE1 protein localizes specifically to the spermatozoa’s acrosome (transcription factors are usually located in the nucleus), where it stays anchored to the inner membrane even after the acrosome reaction has taken place. Recent results suggest that ATCE1 might play a role in the newly formed zygote, possibly as a paternally delivered transcription factor. This might ensure that zygotic genome activation awaits fertilization.
Areas of Interest
Don’s laboratory continues to focus on two areas of interest: molecular factors and pathways regulating gamete production and fertilization, and cell cycle regulation and activation of cancerous processes.