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Departments of Pathology (S.C.C., L.C., K.H.B., M.M.M.)
Molecular and Cellular Biology (M.M.M.), and Molecular and Human
Genetics (K.H.B., M.M.M.) Baylor College of Medicine Houston,
Texas 77030
Program in Molecular Biology (A.K.) Memorial
Sloan-Kettering Cancer Center New York, New York 10021
Tumor suppressors function as antiproliferative
signaling proteins, and defects in these genes lead to uncontrolled
cell proliferation and cancer. For example, absence of the tumor
suppressor p27Kip1, a cyclin-dependent kinase
inhibitor (CKI), results in increased body size, hyperplasia of several
organs including the testes, and cancer in mice. Similarly, lack of
inhibins, 
/ß heterodimeric members of the transforming growth
factor-ß (TGFß) superfamily, causes testicular and ovarian tumors
of the granulosa/Sertoli cell lineage beginning at 4 weeks of age and
adrenal tumors in gonadectomized mice. Neither the cell cycle
alterations in the absence of inhibin nor the cause of the increased
testis size in the p27 knockout mice is known. To study the molecular
(cell cycle) changes that result from absence of inhibins, we analyzed
the regulation of cell cycle proteins in gonadal tumors derived from
inhibin knockout mice (Inha-/-). Northern
blot analyses demonstrate that cyclin-dependent kinase 4 (Cdk4) and
cyclin D2 mRNA levels are elevated, and immunohistochemistry shows that
p27 protein levels are decreased in both ovarian and testicular tumors
from Inha-/- mice. These findings suggest
that increased Cdk4/cyclin D2 (positive) activity and decreased p27
(negative) activity is causal for gonadal tumor formation. To test this
hypothesis, we generated double mutant mice lacking both p27 and
inhibin to determine whether the tumor suppressors p27 and inhibin
have additive suppressor activity in the gonads. Like
Inha-/- mice,
p27-/-Inha-/- mice
demonstrate elevated serum activin levels, ovarian and testicular
tumors, and a resultant lethal cachexia-like syndrome. However, whereas
95% of the Inha-/- female mice die by 18
weeks of age, 100% of the
p27-/-Inha-/-
female mice are dead by 8 weeks. Similarly, 95% of the
Inha-/- single mutant males die by 13 weeks
while 100% of the p27-/-Inha-/-
male mice die by 10 weeks. Moreover, tumor foci in
p27-/-Inha-/- mice
can be observed as early as 2 weeks of age in males and as early as 4
weeks in females. These findings demonstrate that absence of both
inhibin and p27 in mice causes earlier development of ovarian and
testicular tumors and earlier death compared with absence of inhibin
alone.
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