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.
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