DF/HCC Program Affiliation

Breast Cancer

Research Abstract

The laboratory is interested in elucidating molecular mechanisms of the cell cycle and telomere maintenance, as well as in determining how aberrations in these mechanisms leads to cancer and Alzheimer's disease. Phosphorylation of proteins on serines or threonines preceding a proline (pSer/Thr-Pro) is a major regulatory mechanism and its deregulation can lead to cancer and Alzheimer’s disease (AD). Although Ser/Thr phosphorylation is proposed to regulate protein function by inducing conformational changes, little is known about the conformational changes and their significance. Our identification of the peptidyl-prolyl isomerase (PPIase) Pin1 that specifically isomerizes only pSer/Thr-Pro bonds in certain proteins led us to identify a new signaling mechanism, whereby prolyl isomerization catalytically induces conformational changes after phosphorylation to regulate their function. Pin1 function is normally tightly regulated and its overexpression plays a pivotal role during oncogenesis. Furthermore, inhibition of Pin1 suppresses cell transformation in vitro and deletion of Pin1 in mice prevents oncogenesis induced by other oncogenes such as Ras, or Neu. Interestingly, Pin1 expression inversely correlates with the predicted neuronal vulnerability and actual neurofibrillary degeneration in AD. Moreover, Pin1 is the first gene whose knockout in mice causes progressive age-dependent neurodegeneration and tauopathies. These results open a new idea for understanding the pathogenesis of cancer and Alzheimer's disease and designing their therapies.

Telomeres are critical for maintaining genomic stability and allowing cells escaping from crisis, and their deregulation has been implicated in cancer and premature aging. We have identified the telomeric protein Pin2/TRF1 and its interacting proteins, PinX1-4. PinX1 is the first endogenous telomerase catalytic inhibitor and is a putative tumor suppressor. These studies should yield new insights into telomere maintenance, cell growth control and oncogenesis, and may lead to the development of new anticancer therapy.

Our future directions are to elucidate how protein phosphorylation regulates cell growth, how deregulation of Pin1 leads to cell transformation and Alzheimer’s disease, how telomerase and telomerase inhibitors are regulated, how deregulation of telomerase and telomerase inhibitors contributes to cancer and aging, and how to use our new insights into the pathogenesis of cancer and Alzheimer’s disease to design more effective therapies.

Publications

• Lu KP, Suizu F, Zhou XZ, Finn G, Lam P, Wulf G.Targeting carcinogenesis: a role for the prolyl isomerase Pin1?.Mol Carcinog 2006 Jun;45(6):397-402.
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• Pastorino L, Sun A, Lu PJ, Zhou XZ, Balastik M, Finn G, Wulf G, Lim J, Li SH, Li X, Xia W, Nicholson LK, Lu KP.The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production.Nature 2006 Mar 23;440(7083):528-34.
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• Wulf G, Garg P, Liou YC, Iglehart D, Lu KP.Modeling breast cancer in vivo and ex vivo reveals an essential role of Pin1 in tumorigenesis.EMBO J 2004 Aug 18;23(16):3397-407.
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• Lu KP.Pinning down cell signaling, cancer and Alzheimer's disease.Trends Biochem Sci 2004 Apr;29(4):200-9.
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• Liou YC, Sun A, Ryo A, Zhou XZ, Yu ZX, Huang HK, Uchida T, Bronson R, Bing G, Li X, Hunter T, Lu KP.Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration.Nature 2003 Jul 31;424(6948):556-61.
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• Zhou XZ, Lu KP.The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor.Cell 2001 Nov 2;107(3):347-59.
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• Lu PJ, Wulf G, Zhou XZ, Davies P, Lu KP.The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein.Nature 1999 Jun 24;399(6738):784-8.
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• Lu PJ, Zhou XZ, Shen M, Lu KP.Function of WW domains as phosphoserine- or phosphothreonine-binding modules.Science 1999 Feb 26;283(5406):1325-8.
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