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Hong Zhang, Ph.D.Academic Role: Assistant Professor
Faculty Appointment(s) In:
Other Affiliation(s):
Genetic Regulation of Senescence in Aging and Cancer Molecular Targeting of E3 Ligase in Oncogenesis
Genetic Regulation of Senescence in Aging and CancerNormal somatic cells cannot divide indefinitely, and at the end of their replicative lifespan, they enter an irreversible growth arrest state termed replicative senescence. It is now known that replicative senescence is activated by progressive telomere shortening during successive cell divisions. Since its discovery, senescence has been proposed to contribute to the aging process and act as a tumor suppressor. In complex organisms such as mammals, many somatic tissues are capable of renewal, repair, and even regeneration. Renewable tissues allow organisms to replace damaged cells, offering a clear advantage over post-mitotic tissues found in worm or fruit fly. The senescence theory of aging proposes that gradual accumulation of senescent cells in adult organisms is contributing to the complex aging phenotypes by depleting the renewal capacity of tissues and/or by interfering tissue homeostasis and functions. While the critical evidence supporting its role in aging is missing, increasing evidence suggests that senescence is a tumor suppression mechanism. As tumorigenesis is a multi-step process in which a normal cell acquires genetic changes in a number of critical cancer causing genes, senescence limits proliferative capacity of a cell and consequently impedes the accumulation of multiple mutations necessary for tumorigenesis. In contrast to normal somatic cells, cancer cells can divide indefinitely in culture and immortality is one of the hallmarks of cancer cells. Consistently, both p53 and pRb, two major tumor suppressor genes whose mutations are most common in cancers, are the critical mediators of replicative senescence. My lab is interested in understanding the genetic events that activate replicative senescence. Recently we discovered that Smurf2 is up-regulated in response to telomere attrition during replicative senescence in human fibroblasts, and expression of telomerase reverse transcriptase (hTERT) prevents such Smurf2 induction. Conversely, adventitious expression of Smurf2 induces the senescence phenotype in early passage cells, and reverses cellular immortalization by hTERT. Furthermore, we found that the senescence-inducing effects of Smurf2 require a novel function distinct from its E3 ubiquitin ligase activity. We are continuing our effort in the characterization of genetic pathways to senescence, focusing on the molecular mechanisms of Smurf2-induced senescence and transcriptional regulation of Smurf2 by telomere shortening. We employ genetic screens in cell culture combined with microarray analysis to identify, characterize, and understand the hierarchal positions of these genetic components in the senescence pathways. Smurf2 is the first gene demonstrated to be both regulated by telomere attrition and sufficient to induce senescence, providing a genetic shortcut to senescence without the requirement of telomere shortening. We are making conditional Smurf2 transgenic and knock-out mouse models to modulate the expression of Smurf2. We hope to manipulate the senescence response by modulating the expression of Smurf2 in a tempo-spatial specific manner. Using these mouse models, we will investigate the underlying mechanisms of senescence contributing to tumor suppression and aging. Molecular Targeting of E3 Ligase in OncogenesisTumors arise from normal cells through a multistep process by acquiring discrete genetic and epigenetic changes. These changes render tumors to evolve progressively towards malignancy. The cellular functions of these changes are often not unique or limited to oncogenesis, but can be also found in many normal physiological processes. The important distinction is that these changes in oncogenesis are dysregulated. One important regulatory mechanism is the regulation of protein degradation by the ubiquitin-proteasome pathway. To carry out proper cellular functions, proteins are dynamically synthesized, modified and degraded. Controlled and selective degradation of proteins is essential for normal cell growth and differentiation. A major protein degradation pathway is the ubiquitin-proteasome pathway, in which ubiquitin molecules are added to target proteins to form polyubiquitin chains, and subsequently the 26S proteasome degrades polyubiquitinated proteins. Since its discovery, the ubiquitin-proteasome pathway has entered the center stage of many important cellular processes. The substrate specificity of ubiquitination is largely determined by hundreds of E3 ligases found in mammals. Consequently, dysregulation of E3 ligases is closely associated with many diseases, including cancer. The E3 protein ligase Smurf2, a member of the HECT family of E3 ligase, has been implicated in the ubiquitination of a number of proteins including Smads, TGF-beta receptors, beta-catenin and others. These potential Smurf2 targets have all been implicated in oncogenesis when dysregulated. Our preliminary studies found that Smurf2 up-regulation can suppress metastasis dependent on its ligase activity. We hypothesize that Smurf2 E3 ligase plays an important role in regulating oncogenesis/metastasis through its ability to ubiquitinate critical proteins involved in these processes. Using tumor xenograft models and the Smurf2 knock-out model, we are investigating the molecular functions of Smurf2 in oncogenesis and metastasis. Using a combination of biochemistry, molecular and cellular biology approaches, we will identify and characterize Smurf2’s protein targets that are responsible for Smurf2 mediated regulation of oncogenesis and metastasis.
Office: S7-125
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55 Lake Avenue North Worcester, MA 01655