Hong Zhang received his B.S. from Fudan University in China and Ph.D. from Michigan State University. He received postdoctoral training at Stanford University School of Medicine, and joined the faculty in the Department of Cell Biology at University of Massachusetts Medical School in 2006. He is a New Scholar in Aging of the Ellison Medical Foundation.
Genetic Regulation of Senescence in Cancer, Aging and Stem Cell Self-renewal; Molecular Targeting of E3 Ligases in Transcriptional Regulation
My lab is interested in the genetic regulation of senescence in cancer, aging and stem cell self-renewal. Senescence, a process by which cells enter an irreversible growth arrest state, is activated by many stimuli, including telomere attrition, aberrant oncogenic signaling, DNA damage or oxidative stress. Increasing evidence suggests that senescence acts as a tumor suppression mechanism. By limiting cell proliferation, senescence impedes the accumulation of multiple mutations that are necessary for tumorigenesis. Furthermore, senescence activated by aberrant oncogenic activation, DNA damage or oxidative stress provides a failsafe mechanism that prevents proliferation of cells at risk of neoplastic transformation. However, cell proliferation is critical for renewal, repair and regeneration to maintain normal tissue homeostasis and functions. By limiting cell proliferation and consequently depleting the renewal capacity of stem or progenitor cells, senescence is thought to contribute to the aging process. Therefore, senescence is regarded as an antagonistic pleiotropy in cancer and aging: benefits organisms for survival and fitness early in life by acting as a tumor suppressor, but has a detrimental effect on the survival and fitness of organisms later in life by contributing to aging. This view of senescence regulation in aging and cancer provides a plausible explanation for the logic of aging and is consistent with the evolutionary theory of aging. The specific projects that are being investigated in the lab are listed below.
Genetic pathways of senescence: Using forward genetic screen as well as reverse genetics, we are interested in elucidating the genetic pathways that govern senescence. Towards this goal, we have identified a number of genes that control senescence activation and will continue to search for additional senescence regulators. We are interested in understanding the underlying molecular mechanisms of senescence regulation by these genes.
Senescence regulation in oncogenesis: To investigate the function of senescence in tumorigenesis, we are generating novel mouse models, in which senescence response is modulated. Our strategy of modulating senescence response in vivo is to manipulate the expression of key senescence regulators identified in our genetic screen studies. One such regulator is Smurf2, an E3 ligase. We have generated a Smurf2-deficient mouse model as well as conditional Smurf2 transgenic mouse models. Our ongoing studies indicate that Smurf2-deficient mouse embryonic fibroblasts exhibit delayed senescence entry and enhanced potential to become immortalized in culture. Furthermore, Smurf2-deficient mice spontaneously develop tumors at higher frequency as compared to wild-type mice, suggesting that Smurf2 is a tumor suppressor. Studies using Smurf2-deficient mice are complemented by our studies using the conditional Smurf2 transgenics. Using these "senescence" mouse models, combined with different tumorigenesis models (for instance, p53 knockout, B cell lymphoma, skin cancer, colon cancer and liver cancer models), we hope to gain a better understanding of the regulation and contribution of senescence in tumor development.
Senescence in aging and stem cell self-renewal: The mouse models we have generated to modulate senescence response in vivo are also used in our studies of senescence regulation in aging, with an emphasis on adult stem cells. For instance, declining hematopoiesis is a well characterized aspect of immune senescence. In aged mice, the self-renewal capacity of long-term hematopoietic stem cells (LT-HSC) diminishes. Our ongoing studies have found that LT-HSC population, which give rise to all lineages of blood cells, increases in Smurf2-deficient mice, suggesting a beneficial effect of Smurf2 deficiency. Studies are designed to investigate whether the function and self-renewal capacity of Smurf2-deficient LT-HSC are enhanced, whether such enhanced function of HSCs provides benefit to mice during aging, and whether senescence plays a role in HSC self-renewal and regulation during aging.
As aging is accompanied by increased susceptibility to all major chronic diseases, including cardiovascular disease, cancer, Alzheimer's disease, diabetes, arthritis and osteoporosis, we are taking a systematic approach to analyze the impact of senescence on stem cell self-renewal in various tissues/organs, including bone marrow, bone, skin, pancreas, brain and kidney. Understanding the underlying mechanisms of age-associated decline in the renewal capacity of stem cells will help us gain better understanding of aging.
Molecular targeting of E3 ligase in transcriptional regulation: Smurf2 belongs to the Nedd4 family of E3 ligase. In mammals, all nine members share similar structure features: N-terminal C2 domain, C-terminal catalytic HECT domain and 2-4 WW domains in the middle to mediate protein-protein interaction with substrates. WW domain is known to interact with PPXY motif in substrates, yet how such interaction determines substrate specificity is not clear. PPXY motif is found in many transcription factors, including those involved in TGF-? signaling, Wnt signaling, and polycomb complex. Using an unbiased genetic screen, we are interested in identifying E3 ligases that are responsible for the ubiquitination of these important transcriptional factors, the consequence of dysregulation of such ubiquitination in diseases including cancer, and the specificity of substrate recognition by different members of the Nedd4 family of E3 ligases.
Figure 1. Microarray analysis of senescence induced by Smurf2 vs. replicative senescence
Figure 2. Smurf2-deficient mice exhibit increased spontaneous tumorigenesis
Figure 3. Smurf2-deficient mice have increased hematopoietic stem cell population (Lin-c-kit++Sca1+ CD150+CD135-)
Figure 4. Smurf2 ubiquitinates transcriptional repressor Id1