Kap usa8/18/2023 ![]() Together, these data suggest that KAP plays a role in normal growth control and that deregulated KAP expression may contribute to the malignant phenotypes. ![]() In addition, blocking KAP overexpression resulted in a decreased population of S-phase cells during cell cycle progression and reduced Cdk2 kinase activity. We demonstrate further that selective inhibition of KAP overexpression by an antisense approach in the HeLa and LNCaP cancer cell lines decreased their transformed phenotype in vitro and their tumorigenicity in nude mice. We report that breast and prostate malignancies are associated with high levels of KAP expression. ![]() In an effort to search for candidate genes whose function or expression is altered causally in carcinogenesis, we identified the KAP gene as an overexpressed gene in human breast and prostate cancer using differential screening. Phosphatases have also been shown to play an important role in regulating a variety of signal transduction pathways that have a bearing on cancer (reviewed in references 5, 9, 29, 31, 36, and 39). However, the physiological substrate(s) for tyrosine dephosphorylation of KAP has not yet been identified.Īccumulating evidence suggests that deregulation of protein phosphorylation is a key event in neoplastic transformation. It has been reported that KAP may inactivate a specific protein kinase, probably Cdk2 or Cdc2, by removing phosphates from the cyclin complexes, and this may contribute to cell cycle control ( 2, 24, 42). However, the biological significance of the interactions remains to be elucidated. Further studies demonstrated that kinase-associated phosphatase (KAP) binds to Cdk2 and dephosphorylates Thr160 when the associated cyclin subunit is degraded or dissociated ( 2, 42). The identification of these negative regulators of Cdks has provided key insights into how the cell cycle can be controlled.Ī Cdk-interacting protein called KAP/Cdi1 was first identified as a novel G 1- and S-phase dual-specificity phosphatase that associates with Cdk2 and/or Cdc2 ( 22, 24). Among these, the mammalian G 1 Cdk inhibitors have been shown to be involved in diverse processes such as repair of DNA damage, differentiation, tumor suppression, and cellular senescence ( 12, 22, 24, 25, 37, 52). Proteins that interact with Cdks play distinct and specific roles in cell cycle regulation. The activity of these kinases depends on their association with a family of positive regulatory protein subunits known as cyclins during the cell cycle. These controls play important roles in preventing tumorigenesis ( 26, 28, 30, 31).Ĭell cycle progression in mammals requires multiple cyclin-dependent kinases (Cdks) ( 44). The transition from one stage of the cell cycle to another is regulated by the transcription of a number of cyclin genes, the degradation of cyclin proteins, and the modification of the cyclin-dependent kinase proteins by phosphorylation (reviewed in references 11, 29, and 30). Among normal cellular functions, regulatory control of the cell cycle plays an important role in normal cell proliferation, and genetic alterations that affect cell cycle control have been shown to be associated with tumor progression (reviewed in references 26, 28, 30, 32, 44, and 46). These alterations may involve the dysregulation of a variety of normal cellular functions, leading to the initiation and progression of a tumor. Human cancer development is a multistage process that results from the stepwise acquisition of genetic alterations. These findings suggest that therapeutic intervention might be aimed at repression of KAP gene overexpression in human breast and prostate cancer. Furthermore, lowering KAP expression led to inhibition of the transformed phenotype, with reduced anchorage-independent growth and tumorigenic potential in athymic nude mice. Blocking KAP expression by antisense KAP in a tetracycline-regulatable system results in a reduced population of S-phase cells and reduced Cdk2 kinase activity. In normal cells, KAP is primarily found in the perinuclear region, but in tumor cells, a significant portion of KAP is found in the cytoplasm. Here we report that breast and prostate malignancies are associated with high levels of KAP expression. We have identified the KAP gene as an overexpressed gene in breast and prostate cancer by using a phosphatase domain-specific differential-display PCR strategy. ![]() The kinase-associated phosphatase (KAP) is a human dual-specificity protein phosphatase that was identified as a Cdc2- or Cdk2-interacting protein by a yeast two-hybrid screening, yet the biological significance of these interactions remains elusive. Accumulating evidence suggests that phosphatases play an important role in regulating a variety of signal transduction pathways that have a bearing on cancer.
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