This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wysolmerski, J. J. Articles by Philbrick, W. M. Search for Related Content PubMed PubMed Citation Articles by Wysolmerski, J. J. Articles by Philbrick, W. M.

Transactivation of the PTHrP Gene in Squamous Carcinomas Predicts the Occurrence of Hypercalcemia in Athymic Mice¹

Department of Medicine [J. J. W., J. F., A. E. B., W. M. P.] and Section of Comparative Medicine [E. C. W.], Yale University School of Medicine, New Haven, Connecticut 06510; Section of Endocrinology, West Haven Veterans Administration Medical Center, West Haven, Connecticut 06516 [R. V., W. J. B.]; Section of Endocrinology, Veterans Administration West Side Medical Center, Chicago, Illinois 60612 [S. C. K.]; and Department of Medicine, University of Texas Health Sciences Center, San Antonio, Texas 78284 [T. A. G.]

Humoral hypercalcemia of malignancy (HHM) is caused by the secretion of parathyroid hormone-related protein (PTHrP) by tumor cells, and tumors of squamous histology are the ones most commonly complicated by HHM. To determine why some squamous tumors cause HHM and others do not, we quantitated the levels of PTHrP mRNA expression and PTHrP secretion in a series of eight squamous tumor lines. As anticipated, we found that the level of PTHrP mRNA expression in individual lines correlated with their PTHrP secretion rates. However, PTHrP mRNA levels varied widely in individual lines, and only those tumor lines with the highest levels of PTHrP gene expression were able to cause hypercalcemia in athymic mice. We found that a specific segment of the PTHrP promoter could reproduce the relative pattern of PTHrP gene expression when cloned in front of a chloramphenicol acetyltransferase reporter gene and transiently transfected into these squamous lines. Deletional analysis confirmed that specific sequences within the PTHrP gene promoter appeared to be involved in the transactivation of the gene in tumor lines expressing high levels of PTHrP mRNA. These data suggest that the ability of a given squamous tumor to cause HHM is ultimately a function of its level of PTHrP gene expression, which in turn appears to be a function of the ability of specific transcription factors to transactivate PTHrP gene expression.

¹ This work was supported by Grant BE-152C from the American Cancer Society (to W. M. P.) and Grant CA 09331 from the NIH (to J. J. W.).

² To whom requests for reprints should be addressed, at Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, P.O. Box 3333, New Haven, CT 06510-8056.

Received 10/10/95. Accepted 1/ 2/96.

This article has been cited by other articles:

				Y. Yen, P. G. Chu, and W. Feng Paraneoplastic Syndromes in Cancer: CASE 3. Parathyroid Hormone-Related Hypercalcemia in Cholangiocarcinoma J. Clin. Oncol., June 1, 2004; 22(11): 2244 - 2245. [Full Text] [PDF]

				A. Slominski and J. Wortsman Neuroendocrinology of the Skin Endocr. Rev., October 1, 2000; 21(5): 457 - 487. [Abstract] [Full Text]

				T. A. Guise and G. R. Mundy Cancer and Bone Endocr. Rev., February 1, 1998; 19(1): 18 - 54. [Abstract] [Full Text]