Professor, Department of Medicine (Gastroenterology & Liver Diseases)
Interim Chair, Department of Developmental & Molecular Biology
The retinoblastoma protein (pRb) is a prototype tumor suppressor. In addition to retinoblastomas, pRb mutations have been found in cancers of the bone, lung, bladder, and prostate. Our laboratory is studying how pRb suppresses tumorigenesis.
(1) The best-established biochemical function of pRb is repression of the transcription factor E2Fs, resulting in inhibition of proliferation genes. This model suggests that overly active E2F activity following loss of pRb causes tumorigenesis. Knockout of various E2Fs can delay tumorigenesis following pRb loss in mice, demonstrating the importance of E2F. Using a kinetic approach, we identified the E3 ubiquitin ligase Skp2 as a pRb target (Ji et al 2004). We discovered that deleting Skp2 alone is sufficient to completely block tumorigenesis following pRb loss in mouse models. We further determined that the functional mechanism underlying this essential role of Skp2 is to ubiquitinate p27 after it is phosphorylated on the Thr187 residue (Wang et al 2010). Our study established a pRb-Skp2-p27T187p pathway in pRb function that is essential for tumorigenesis following pRb loss. A major current project is to extend this pathway further downstream.
(2) The reason for the cell type specific patterns of pRb mutations in cancer is another major research interest in our lab. We hypothesized that certain functions of pRb may depend on certain cell type-specific regulators. Using this rationale, we discovered an apoptosis inducing activity of Rb that is dependent on the androgen receptor in prostate cancer cells (Wang et al 2004). We further determined that the pRb target Skp2 is downstream of AR in androgen-induced proliferation of prostate cancer cells (Wang et al 2008). Currently we are studying how AR regulates Skp2.
(3) A third line of research in the lab is to study the roles of pRb and related regulators in the liver and in hypothalamus neurons that govern energy metabolism. Hepatocytes can regenerate when liver functions are insufficient. We demonstrated that inactivation of the cyclin-dependent kinase inhibitor p27 can increase hepatocyte proliferation after their transplantation into failing livers to treat liver failure (Karnezis et al 2001). We recently discovered important roles of pRb in hypothalamus arcuate nucleus POMC neurons in controlling eating and body weight. Inactivation of pRb in these neurons leads to early onset obesity and type 2 diabetes (unpublished). These studies will improve our understanding of obesity and diabetes to lead to novel strategies to treat them.
Karnezis, A.N., Dorokhov, M., Grompe, M., Zhu, L. Loss of p27Kip1 enhances the transplantation efficiency of hepatocytes transferred into diseased livers. J Clin Invest. 2001 Aug;108(3):383-90.
Ji P, Jiang H, Rekhtman K, Bloom J, Ichetovkin M, Pagano M, Zhu L. An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutant. Mol Cell. 2004 Oct 8;16(1):47-58.
Wang X, Deng H, Basu I, Zhu L. Induction of androgen receptor-dependent apoptosis in prostate cancer cells by the retinoblastoma protein. Cancer Res. 2004 Feb 15;64(4):1377-85.
Wang H, Sun D, Ji P, Mohler J, Zhu L. An AR-Skp2 pathway for proliferation of androgen-dependent prostate-cancer cells. J Cell Sci. 2008 Aug 1;121(Pt 15):2578-87.
Wang H, Bauzon F, Ji P, Xu X, Sun D, Locker J, Sellers RS, Nakayama K, Nakayama KI, Cobrinik D, Zhu L. Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/- mice. Nat Genet. 2010 Jan;42(1):83-8.
Zhu L. Skp2 knockout reduces cell proliferation and mouse body size: and prevents cancer? Cell Res. 2010 Jun;20(6):605-7.
Lu Z, Marcelin G, Bauzon F, Wang H, Fu H, Dun SL, Zhao H, Li X, Jo YH, Wardlaw S, Dun N, Chua S Jr, Zhu L. pRb is an obesity suppressor in hypothalamus and high-fat diet inhibits pRb in this location. EMBO J. 2013 Mar 20;32(6):844-57.
Zhao H, Bauzon F, Fu H, Lu Z, Cui J, Nakayama K, Nakayama KI, Locker J, Zhu L. Skp2 deletion unmasks a p27 safeguard that blocks tumorigenesis in the absence of pRb and p53 tumor suppressors. Cancer Cell. 2013 Nov 11;24(5):645-59.
Lu Z, Bauzon F, Fu H, Cui J, Zhao H, Nakayama K, Nakayama KI, Zhu L. Skp2 suppresses apoptosis in Rb1-deficient tumours by limiting E2F1 activity. Nat Commun. 2014 Mar 17;5:3463.
More Information About Dr. Liang Zhu
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Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Ullmann Building, Room 521
Bronx, NY 10461