Professor, Department of Medicine (Gastroenterology & Liver Diseases)
Interim Chair, Department of Developmental & Molecular Biology
CONTROL OF TUMORIGENESIS, OBESITY, AND REGENERATION BY TUMOR SUPPRESSORS AND ONCOPROTEINS
A common feature shared by cancer, obesity, and tissue regeneration is deregulation of cellular homeostasis, including cell proliferation, cell growth, cell metabolism, and cell death. Tumor suppressors such as pRb and p53, oncoproteins such as Ras and Myc, and organ size regulators such as YAP, are the major regulators of these aspects of cellular homeostasis. We are studying how these regulators regulate these aspects.
In the cancer field, we are identifying treatment strategies for tumors that have permanently lost the tumor suppressor pRb or both pRb and p53 using mouse tumor models. pRb and p53 are the two major tumor suppressors. Their functions are activated by oncogenic events and they implement most and best cells’ antitumor mechanisms to safeguard against tumorigenesis. When tumorigenesis succeeds, pRb, p53, or both is frequently inactivated. In reverse, reactivation of pRb and p53 are rationale for most antitumor therapeutics. However, when pRb and p53 are genetically inactivated, cells irreparably lose the antitumor mechanisms afforded by them, which may explain why advanced cancers are difficult to treat. We generated mouse tumor models in which the genes for pRb or both pRb and p53 are knocked out to identify mechanisms that can still inhibit these tumors. We showed that combining deletion of Skp2, which is a target of repression by pRb, completely blocked tumorigenesis in the absence of pRb or both pRb and p53 (refs 2, 5, 7, 8). Ongoing studies aim to target functions of Skp2 in regulating p27 degradation, regulating cancer cell metabolism, and regulating epithelial-to-mesenchymal transition to inhibit pRb and p53 doubly deficient tumors.
In the obesity field, we are studying the function of pRb in hypothalamus POMC neurons. These neurons negatively regulate feeding, and it has been suggested that high fat feeding could damage these neurons, which results in more desire to eat. This feed-forward circle may explain why obesity is difficult to treat. We determined that high fat feeding induced or activated a kinase in POMC neurons to phosphorylate and, therefore, functionally inactivate pRb. Interestingly, in this context, inactivation of pRb did not induce tumorigenesis. On the contrary, it induced degenerative changes in POMC neurons. When we deleted pRb in POMC neurons, the mice increased their food intake and become obese, demonstrating that pRb functions to maintain POMC neuron homeostasis to suppress obesity. To our surprise, in AGRP neurons, which reside together with POMC neurons in hypothalamus and functionally antagonize POMC neurons to reduce the desire to feed, pRb function is not important. Deletion of pRb in AGRP neurons did not harm AGRP neuron homeostasis. Based on these findings (ref 6, in collaboration of with Dr. Chua of the Einstein Diabetes Center), we are identifying the kinases that phosphorylate pRb in POMC neurons after high fat feeding, and establishing techniques to prevent pRb phosphorylation following high fat feeding. Through these studies, we aim to block the feed-forward circle to treat obesity.
The liver has remarkable ability to regenerate when more than 70% of it is resected. This regenerative capability has important implication to tumorigenesis and regenerative medicine. Since the supply of donor liver is far smaller than the demand, hepatocyte transplantation is the best approach to treating liver failure and liver defects. We showed that by deleting the cyclin-dependent kinase inhibitor p27, hepatocytes were stimulated to proliferate more in the host liver to save mice from liver failure (ref 1). Unfortunately, deleting p27 also increased liver cancer burden during liver carcinogenesis by chronic HBV or chemical DEN (ref 3, 4). In collaboration with Dr. Shafritz of the Einstein Liver Center, we are now studying the liver size regulator YAP to determine its ability to increase hepatocyte proliferation following transplantation and its associated liver cancer risk.
More Information About Dr. Liang Zhu
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Albert Einstein College of Medicine
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Ullmann Building, Room 521
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