The best-understood function of the Kip family of cdk inhibitors is to inhibit cdk2 and induce cell cycle exit. Our laboratory also showed that p21 also has roles in differentiation, proliferation and tumor development. Furthermore, p21 accumulation is associated with poor prognosis in oligodendroglioma, squamous cell carcinoma, tall cell thyroid cancer, and some breast, prostate and cervical cancers in humans. p21 can interact with a number of non-cyclin-cdk proteins which might explain the role of these proteins in some cancers;however, the significance of any interaction in vivo to tumor development has not been determined. Our preliminary data demonstrates that the ability of p21 to stabilize cyclin D1-cdk4 may be important for the development of ODG induced by PDGF in mice. To understand this further and address its significance in human disease we propose three aims:
Specific aim 1. Complementation studies in animals during tumor development with cellular and biochemical studies in cell lines that recapitulate the PDGF-induced transformation of progenitor cells suggest that p21 promotes ODG by stabilizing cyclin D1-cdk4. To confirm this, we propose to determine how modulating cyclin D1 and cdk4 expression affects tumor progression. Furthermore, a mouse p21 knock-in model will be developed to establish the importance of cyclin-cdk binding for tumor development in this model.
Specific aim 2. p21 expression is related to poor prognosis in human ODG;however, what p21 status reflects about the nature of ODG or the ability to treat patients with the disease is not clear. To address this, we will determine if mouse ODG induced by either other oncogenes or from other progenitor cells is also dependent on p21 induced stabilization of cylcin D1-cdk4. In addition, we will use a 140 human ODG collection to determine whether p21 expression correlates with specific changes activating the PDGF signaling pathway or whether p21 status is reflecting differences in how the incipient tumor cells increase the expression of cyclin D1-cdk4.
Specific aim 3. We understand the process by which cki accumulate during growth arrest, but know nothing about how they accumulate as cells enter the cell cycle. Our data in ODG support the significance of such regulation, and the extant literature shows that it is not unique to the glial lineage. An understanding of growth-regulated accumulation of p21 will be important when considering this as a potential therapeutic target. In this aim, we will examine the post-transcriptional mechanisms regulating p21, and the role that phosphorylation plays in YH cells and during tumor development.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Hildesheim, Jeffrey
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sloan-Kettering Institute for Cancer Research
New York
United States
Zip Code
Liu, Y; Raheja, R; Yeh, N et al. (2014) TRIM3, a tumor suppressor linked to regulation of p21(Waf1/Cip1.). Oncogene 33:308-15
Raheja, Radhika; Liu, Yuhui; Hukkelhoven, Ellen et al. (2014) The ability of TRIM3 to induce growth arrest depends on RING-dependent E3 ligase activity. Biochem J 458:537-45
Pérez-Sanz, J; Arluzea, J; Matorras, R et al. (2013) Increased number of multi-oocyte follicles (MOFs) in juvenile p27Kip1 mutant mice: potential role of granulosa cells. Hum Reprod 28:1023-30
Marchini, Sergio; Poynor, Elizabeth; Barakat, Richard R et al. (2012) The zinc finger gene ZIC2 has features of an oncogene and its overexpression correlates strongly with the clinical course of epithelial ovarian cancer. Clin Cancer Res 18:4313-24
Miller, Jeffrey P; Yeh, Nancy; Hofstetter, Christoph P et al. (2012) p27kip1 protein levels reflect a nexus of oncogenic signaling during cell transformation. J Biol Chem 287:19775-85
Hukkelhoven, Ellen; Liu, Yuhui; Yeh, Nancy et al. (2012) Tyrosine phosphorylation of the p21 cyclin-dependent kinase inhibitor facilitates the development of proneural glioma. J Biol Chem 287:38523-30
Ciznadija, Daniel; Liu, Yuhui; Pyonteck, Stephanie M et al. (2011) Cyclin D1 and cdk4 mediate development of neurologically destructive oligodendroglioma. Cancer Res 71:6174-83
Ciznadija, Daniel; Zhu, Xin-Hua; Koff, Andrew (2011) Hdm2- and proteasome-dependent turnover limits p21 accumulation during S phase. Cell Cycle 10:2714-23
See, W L; Miller, J P; Squatrito, M et al. (2010) Defective DNA double-strand break repair underlies enhanced tumorigenesis and chromosomal instability in p27-deficient mice with growth factor-induced oligodendrogliomas. Oncogene 29:1720-31
Miller, Jeffrey P; Yeh, Nancy; Vidal, Anxo et al. (2007) Interweaving the cell cycle machinery with cell differentiation. Cell Cycle 6:2932-8

Showing the most recent 10 out of 16 publications