Thyroid tumors are the most common endocrine malignancy. It has been estimated that up to 90% of the autopsies performed in this country reveal the presence of slow-growing thyroid tumors. While the prognosis for patients with well-differentiated follicular and papillary thyroid tumors is good, anaplastic thyroid tumors are rapidly fatal. Activating Ras mutations are particularly prevalent in human thyroid tumors. Ras mutations are found in benign adenomas and at a higher frequency in follicular and anaplastic carcinomas. Mutations in B-Raf, a downstream Ras effector, are the most frequent mutational event in papillary thyroid tumors. These observations support roles for Ras in the initiation and progression of thyroid tumors. A large proportion of papillary thyroid tumors exhibit amplification and rearrangement of the PKCepsilon gene, leading to the expression of an N-terminal fragment of PKCepsilon structurally similar to the V1 domain, a peptide that selectively inhibits PKCepsilon translocation. Interestingly, most papillary thyroid tumors exhibit decreased expression of PKCepsilon. Moreover, expression of the RET/PTC oncogene induced the selective translocation, followed by downregulation of PKCepsilon. PKCalpha expression is increased in follicular thyroid tumors, tumors that also harbor Ras mutations. It is our hypothesis that individual PKC isozymes play essential roles in the initiation and maintenance of thyroid cell transformation by Ras. Our preliminary data demonstrate that PKCdelta selectively reproduces the acute effects of oncogenic Ras on aberrant cell cycle progression and apoptosis; that PKCepsilon is required for Ras-induced morphological changes; that PKCs mimic the inhibitory effects of Ras on thyroid differentiation; and that Ras-transformed thyroid cells exhibit alterations in PKC expression and activity. The proposed studies investigate the roles of individual PKC isozymes in the initiation and maintenance of Ras transformation in rat thyroid cells. This will be accomplished using highly specific molecular reagents including adenoviruses for PKC isozymes, selective PKC peptide activators and inhibitors and RNA interference. This analysis will provide novel insight into the molecular mechanisms through which Ras dysregulates thyroid cell proliferation, differentiation and survival, and may give rise to the development of new strategies to selectively impair tumor cell proliferation and/or reactivate differentiated gene expression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA109543-01A1
Application #
6918452
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Yassin, Rihab R,
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$264,302
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Nellore, Anoma; Paziana, Karolina; Ma, Changqing et al. (2009) Loss of Rap1GAP in papillary thyroid cancer. J Clin Endocrinol Metab 94:1026-32
Santiago-Walker, Ademi E; Fikaris, Aphrothiti J; Kao, Gary D et al. (2005) Protein kinase C delta stimulates apoptosis by initiating G1 phase cell cycle progression and S phase arrest. J Biol Chem 280:32107-14