@entity5 suppressors function as antiproliferative signaling proteins, and defects in these genes lead to uncontrolled cell proliferation and @entity5 . For example, absence of the @entity5 suppressor @entity7919 ( @entity7919 ), a cyclin-dependent kinase inhibitor (CKI), results in increased body size, @entity1373 of several organs including the testes, and @entity5 in @entity19 . Similarly, lack of inhibins, alpha/beta heterodimeric members of the transforming growth factor-beta (TGFbeta) superfamily, causes @entity43 of the granulosa/Sertoli cell lineage beginning at 4 weeks of age and @entity5 in gonadectomized @entity19 . Neither the cell cycle alterations in the absence of inhibin nor the cause of the increased testis size in the @entity7919 knockout @entity19 is known. To study the molecular (cell cycle) changes that result from absence of inhibins, we analyzed the regulation of cell cycle proteins in @entity5 derived from inhibin alpha knockout @entity19 ( @entity21600 (-/-)). Northern blot analyses demonstrate that @entity11953 ( @entity11953 ) and @entity6834 mRNA levels are elevated, and immunohistochemistry shows that @entity7919 protein levels are decreased in both @entity43 from @entity21600 (-/-) @entity19 . These findings suggest that increased @entity11953 / @entity6834 (positive) activity and decreased @entity7919 (negative) activity is causal for @entity5 formation. To test this hypothesis, we generated double mutant @entity19 lacking both @entity7919 and inhibin alpha to determine whether the @entity5 suppressors @entity7919 and inhibin have additive suppressor activity in the gonads. Like @entity21600 (-/-) @entity19 , @entity7919 (-/-) @entity21600 (-/-) @entity19 demonstrate elevated serum activin levels, @entity43 , and a resultant @entity3085 . However, whereas 95% of the @entity21600 (-/-) female @entity19 die by 18 weeks of age, 100% of the @entity7919 (-/-) @entity21600 (-/-) female @entity19 are dead by 8 weeks. Similarly, 95% of the @entity21600 (-/-) single mutant males die by 13 weeks while 100% of the @entity7919 (-/-) @entity21600 (-/-) male @entity19 die by 10 weeks. Moreover, @entity5 foci in @entity7919 (-/-) @entity21600 (-/-) @entity19 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 @entity7919 in @entity19 causes earlier development of @entity43 and earlier @entity204 compared with absence of inhibin alone.

Inhibin and XXXX interact to regulate gonadal tumorigenesis.

@entity43 :: ('MESH:D010051', 'Disease') :: ['ovarian and testicular tumors', 'testicular and ovarian tumors'] @entity7919 :: ('12576(Tax:10090)', 'Gene') :: ['p27', 'Kip1'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'gonadal tumor', 'adrenal tumors', 'cancer', 'Tumor', 'gonadal tumors'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity1373 :: ('MESH:D006965', 'Disease') :: ['hyperplasia'] @entity6834 :: ('12444(Tax:10090)', 'Gene') :: ['cyclin D2'] @entity3085 :: ('MESH:D002100', 'Disease') :: ['lethal cachexia-like syndrome'] @entity11953 :: ('12567(Tax:10090)', 'Gene') :: ['cyclin-dependent kinase 4', 'Cdk4'] @entity21600 :: ('16322(Tax:10090)', 'Gene') :: ['Inha'] @entity204 :: ('MESH:D003643', 'Disease') :: ['death']
@entity7919 :: (12576(Tax:10090),Gene) :: ['p27']
