© 1992 by Oxford University Press
Journal of the National Cancer Institute, Vol. 84, No. 20, 1565-1571,
October 21, 1992
© 1992 Oxford University Press
Increased Activity of Type I Regulatory Subunit of Cyclic Adenosine 3', 5'- Monophosphate-Dependent Protein Kinase in Estrogen- Induced Pituitary Tumors
Laboratotio de Bioquímica Neuroendócrina, instituto de biologia y Medicina Experimental Buenos Aires, Argentina
*Correspondence to: Alejandro F. De Nicola, M.D., Ph.D., Laboratorio de Bioquímica Neuroendócrina, Institute de Biologia y Medicina Experimental, Obligado 2490, 1428 Buenos Aires, Argentina.
Background: Previous studies have shown that binding of [3H]cyclic adenosine 3‘, 5’- monophosphate(cAMP) is increased in cytosol of diethylstilbestrol (DES)- induced pituitary tumors. In tumor cells, the cAMP-binding proteins that stimulate cell proliferation have been shown to predominate over those that inhibit it. Purpose: This study was designed to determine the type of regulartory subunit(R) of cAMP- depentent protein kinase (PK) responsible for this binding by determining the type of subunit that is incerased in DES-induces pituitary tumors. Methods: Experiments were carried out on three groups of Fischer 344 rats: 1) rats with DES-induced pituitary tumors, 2) ovariectomized rats receiving short- term estrogen trestment with estradiol benzoate (E2) for 4 days, and 3) ovariectomized control rats. We performed immunoprecipitation of RI and RII subunits with polyclonal antibodies in pituitary cytosol (direct method) or after separation of subunits by DEAE- cellulose chromatography (indirect method). The concentration of cAMP was also quantifeid by radioimmunoassay in pituitaries from the three gruoups. Results: Direct immunoprecipitation with RI antibody demonstrated a statistically signficant increase in [3H]cAMP bound to RI in rats receiving E2 for 4 days over that for control rats and an even more significant increase in rats with DES- induced pituitary tumors. There was little change in the nucleotide [3]HcAMP bound to RII. Immunoprecipitation of the eluted fractions after chromatography demonstrated an RI subunit in peaks 1 AND 2. whereas RII was contained almost exlusively in peak 2. After chromatography (indirect method), immunoprecipitation with RI and RII antibody indicated an overall increase in the level of binding to RI protein in tumors. Levels of cAMP in DES-induced pituitary tumors were also high compared with levels in controls or in glands from estrogen- treated rats. Conclusions: In DES- induced pituiary tumors, cAMP may be preferentially bound to one isozyme of PK, which supports current theories that cell proliferation and tumor growth correlate with high expression of the RI subunit. Impications: We plan studies to investigate the effects on tumor growth of the site-selective analogue 8-chloro-cAMP, which binds to RII and causes the elevated levels of the RI subunit of the tumor cells to return to normal levels. [J Natl Cancer Inst 84:1565–1571, 1992]
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