The pocket protein family members, pRb, p107 and p130, are negative regulators of the cell cycle. But, while the role of pRB as a tumor suppressor has been extensively established, genetic inactivation of p107 or p130 is uncommon in tumors. Previous studies have shown that p130 cooperates with the CDK inhibitor p27Kip1 restricting proliferation of mouse intermediate lobe pituitary cells. Accordingly double knockout mice show higher incidence of pituitary tumors than single KO animals. Because of functional redundancy between p130 and p107, to study contributions of p107 as a tumor suppressor we have generated p107+/−; p130−/− mice and combined them with p27 inactivation (5/6KO strain).
We found that reduction of p107 gene dosage caused a significative reduction in tumor-free survival time. As previously described, p27 deficient mice developed adenomas almost exclusively in the pituitary and adrenal medulla, while p130 mutation collaborated to increase the frequency of pituitary and adrenal tumors. In this context, 5/6KO mice showed accelerated appearance of pituitary tumors, while the pheocromocytomas, mostly unilateral in p27 null and DKO mice, where bilateral with almost complete penetrance. Strikingly, microscopic examination of pituitary tumors revealed that in the case of 5/6KO mice tumors were clearly invasive and showed features of aggressive carcinomas.
When we studied the expression of cell cycle regulators, we found than wildtype intermediate lobe has undetectable amounts of p107. This finding was confirmed in extracts from p27 deficient adenomas. Nevertheless, p107 protein was detected in p130 null animals, suggesting a mechanism of compensatory expression. Moreover, by both RT-PCR and immunoblot we found that p107 was still expressed in tumors arising in the 5/6KO mice, indicating that p107 can act as a haploinsufficient tumor suppressor in mouse pituitary.
03 - 07 May 2008
European Society of Endocrinology