Philip Hinds, PhD Principal Investigator Philip Hinds PhD, Princeton University, Princeton NJ Postdoctoral Training, Whitehead Institute, Cambridge, MA Our research is focused on G1 cell cycle control and its dysregulation in cancer cells. Specifically, we are investigating the function of the retinoblastoma protein, (pRb), D-type cyclins, cdk4 and cdk6 in programs of cell cycle exit. Together, along with p16INK4a, a negative regulator of cdk4 and cdk6, these proteins regulate a critical decision making point in progression to S phase and thus DNA replication. In almost all human tumors, one of these proteins is lost or overexpressed, thus favoring proliferation and tumor growth. Although these proteins regulate S phase in response to genome integrity (DNA damage), we and others have shown that they are also critically involved in the permanent cell cycle withdrawal associated with differentiation and senescence. Using complementary approaches incorporating biochemical methods, cell culture of primary and established cells, and animal models of development and cancer, we aim to identify key regulators of tumorigenesis with particular emphasis on breast cancer and osteosarcoma.

Nelson Brown, PhD Research Fellow Nelson Brown

Miriam German Graduate Student Miriam German

Volkan Gunduz Graduate Student Volkan Gunduz

Miaofen Hu, PhD Research Fellow Miaofen Hu MD, Wenzhou Medical College, China PhD, Boston University School of Medicine, Boston, MA Postdoctoral, Oral Medicine and Pathology, Harvard School of Medicine, Boston, MA Postdoctoral, Pathology, Harvard Medical School, Boston, MA Postdoctoral, Radiation Oncology, Tufts University School of Medicine, Boston, MA Since cyclin D-dependent kinases (CDK4/6) play a pivotal role linking growth regulatory signals to cell division, activity of these kinases is very tightly controlled. Deregulated activity of cdk4 or cdk6 can lead to inappropriate cellular proliferation and tumorigenesis as shown by overexpression or activation of CDK4 /6 in some brain cancers, melanoma, and oral cancer. Although it is clear that cdk4 can act as an oncogene at least in part by evading inhibition by p16INK4a, the role of cdk6 in tumorigenesis is less well understood. The overall goal of this project is to better understand the role of CDK4/6 in tumorigenesis and to identify the mechanism by which CDK4/6 contribute to tumor development. To achieve a direct test for function of CDK4 and CDK6 in the process of tumorigenesis, we will make and test hpRNA constructs targeting CDK4/6. These will be used to assess the role of these enzymes in different tumor cell lines and to attempt to study the process of senescence in these cells. Further, to complement these studies in vivo, we will "knock in" mutant alleles of CDK6 in mice that will be invaluable in testing the role of this enzyme in different cancer models, as well as in epithelial differentiation.

Rinath Jeselsohn, MD Postdoctoral Fellow Rinath Jeselsohn

Elizabeth Kong Graduate Student Elizabeth Kong

Daqin Mao Graduate Student Daqin Mao BS, Fudan University, Shanghai, PR China MS, Medical School of Fudan University, Shanghai, PR China Cellular senescence is a process characterized by irreversible cell cycle exit, extensive cytoskeletal changes and expression of â-galactosidase activity. The retinoblastoma tumor suppressor gene (RB)is thought to be a key regulator of cellular senescence. Reintroduction of pRb in human tumor cells that lack it results in premature senescence-like changes. Work in our lab has shown that the induction of senescent phenotype by pRb requires post-mitotic kinase cdk5, a kinase that has heretofore been considered to be almost solely involved in regulating neuronal activities. Activation of cdk5 in neurons depends on its activators p35 and p39, however, little is known how cdk5 is activated in senescent cells. My study focuses on the mechanism of senescence - associated CDK5 activation. And to better understand the biological role of cdk5, I?d also like to explore the consequences of constitutive or acute loss of cdk5 on cell proliferation and tumorigenesis.

Haisu Yang, PhD Research Fellow Haisu Yang BS, Peking University, Peking, PR China PhD, University of Texas Health Science Center, San Antonio, TX Postdoctoral, Pathology, Harvard Medical School, Boston, MA Postdoctoral, Molecular Oncology, Tufts University School of Medicine, Boston, MA A fundamental characteristic of normal cells is their limited ability to proliferate in vitro. This decrease in cell division is virtually irreversible and complete. The progression of events from actively dividing cells to nondividing cells is termed "cellular senescence." My research focuses on studying the mechanism of senescence which has been linked to human aging and tumor suppressive mechanism. The retinoblastoma tumor suppressor protein, pRb, plays an important role in cellular senescence. My previous studies have demonstrated that pRb regulates the expression of cytoskeletal ERM (ezrin, moesin and radixin) proteins in senescent cells. pRb expression results in the activation of Cdk5 which in turn phosphorylates ezrin with subsequent membrane association and induction of cellular shape changes. My projects have been carried out to further identify the biochemical processes that contribute to the senescent associated morphology and explore the consequences of cellular senescence that relate to aging and growth of tumors.