Disease relevance of CDKN1B

• Several lines of evidence from clinical studies and laboratory experiments demonstrate that CDKN1B is an important tumor suppressor gene in prostate cancer etiology [1].
• Biallelic alterations of both ETV6 and CDKN1B genes in a t(12;21) childhood acute lymphoblastic leukemia case [2].
• Finally, the loss of CDKN1B in advanced-stage neuroblastoma suggests this protein may play a role in the neuroblastoma disease process [3].
• Deletions of CDKN1B and ETV6 in acute myeloid leukemia and myelodysplastic syndromes without cytogenetic evidence of 12p abnormalities [4].
• Seven myeloid malignancies showed deletions restricted to a region, including ETV6 and CDKN1B, which has been reported to be frequently lost in leukemias [5].

High impact information on CDKN1B

• Furthermore, polymerized collagen rapidly suppresses p70 S6 kinase, a possible regulator of p27Kip1 [6].
• Similarly, retinoic-acid-induced transcriptional upregulation of the cell-cycle inhibitor p21Cip1 required normal levels of p300, but not CBP, whereas the reverse was true for p27Kip1 [7].
• Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration [8].
• However, tumor-specific mutations are uncommon in genes encoding cyclin E and the CDK inhibitor p27Kip1, two cell-cycle regulators that are also thought to contribute to tumor progression [9].
• Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients [9].

Chemical compound and disease context of CDKN1B

• In addition, to elucidate the effect of progesterone on the expression of p27, tissues from patients with endometrial hyperplasia were examined before and after the administration of medroxyprogesterone acetate (MPA) for the treatment of this disease [10].
• Tyrosine phosphorylation modulates binding preference to cyclin-dependent kinases and subcellular localization of p27Kip1 in the acute promyelocytic leukemia cell line NB4 [11].
• When nontumorous pituitaries and various adenomas were analyzed for p27 and specific hormone production, growth hormone, luteinizing hormone, and thyroid-stimulating hormone cells and tumors had the highest percentages of cells expressing p27, whereas adrenocorticotrophic hormone cells and tumors had the lowest percentages [12].
• The inhibition of cyclin E/cdk2 by p27Kip1 contributes to G1 arrest of LNCaP following high dose DHT. p27KiP1 may be a key effector of androgen dependent growth modulation in prostate cancer cells [13].
• Involvement of p27Kip1 in G1 arrest by high dose 5 alpha-dihydrotestosterone in LNCaP human prostate cancer cells [13].

Biological context of CDKN1B

• To explore whether CDKN1B might be a direct target of MLL and of MLL-AF4, we used chromatin immunoprecipitation (ChIP) assays and luciferase reporter gene assays [14].
• These findings suggest that variable expression levels of cell-cycle inhibitor genes CDKN2A, CDKN2B, and CDKN1B due to regulatory polymorphisms could indeed influence the risk of childhood pre-B ALL and contribute to carcinogenesis [15].
• The CDKN1B genotype was scored as VV, VG, or GG, again on the basis of the digestion products [16].
• We concluded that the paradoxical expression of CDKN2A in neuroblastoma cannot be explained by inactivation of the tumor-suppressor gene CDKN1B or overexpression of the oncogene ID2 [3].
• FISH analyses and loss of heterozygosity studies have delineated a commonly deleted region in hematological malignancies flanked by ETV6 and CDKN1B on chromosome 12p12 [17].

Anatomical context of CDKN1B

• We found that in the MLL-AF4-induced cell lines, the expression of the cyclin-dependent kinase inhibitor gene CDKN1B was dramatically changed at both the RNA and protein (p27kip1) levels [14].
• We have identified a germ-line nonsense mutation in the human CDKN1B gene in a MEN1 mutation-negative patient presenting with pituitary and parathyroid tumors [18].
• Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade [19].
• In the 1,25-dihydroxyvitamin D3 HL60 cell system, G1 arrest has been shown to be mediated by elevated levels of p27/Kip1 protein [20].
• The p27 gene was localized to chromosome band 12p13 by a combination of somatic cell hybrid and fluorescence in situ hybridization analyses [21].

Associations of CDKN1B with chemical compounds

• These associations were particularly strong in those patients with androgen-independent disease [OR = 2.88 (95% CI, 1.19-6.97) and 2.11 (95% CI, 1.05-4.22) for high-risk genotypes of CDKN1A and CDKN1B, respectively] [16].
• Genetic or chemical blockade of the ERK pathway prevented down-regulation and cytoplasmic localization of p27Kip1 in response to estrogen [22].
• 17beta-Estradiol treatment increased Skp2 expression in MCF-7 cells; however, this increase was prevented by G1 blockade mediated by p16Ink4a or the CDK inhibitor roscovitine, whereas down-regulation of p27Kip1 was maintained [22].
• Retinoic acid stabilizes p27Kip1 in EBV-immortalized lymphoblastoid B cell lines through enhanced proteasome-dependent degradation of the p45Skp2 and Cks1 proteins [23].
• Treatment with Leptomycin B (LMB) blocked the translocation of p27Kip1 to the cytoplasm and prevented its degradation, indicating that CRM1-dependent nuclear export is required for p27Kip1 degradation [23].

Physical interactions of CDKN1B

• Interestingly, pRb2/p130 expression negatively modulated the binding of p27Kip1 to JCV TAg [24].
• PURPOSE: Skp2 interacts with the degradation of cyclin-dependent kinase inhibitor p27 [25].
• MLL-AF4 binds to the CDKN1B promoter in vivo and regulates CDKN1B promoter activity [14].
• In addition, studies with p27Kip1 point mutations revealed a decisive role of Tyr88 and Tyr89 in binding to cdk4 [11].
• Vitamin D3 receptor/Sp1 complex is required for the induction of p27Kip1 expression by vitamin D3 [26].

Regulatory relationships of CDKN1B

• In contrast, p27Kip1 antisense oligonucleotides abrogated the growth arrest induced by PTEN [27].
• The F-box protein Skp2 (Fbl1) is a positive regulator of G1-S transition and promotes ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27 [28].
• Increased expression of the P27KIP1 protein in human esophageal cancer cell lines that over-express cyclin D1 [29].
• In this review, we discuss currently available data regarding the multiple signaling targets and pathways by which HER2-targeting antibodies upregulate p27Kip1 protein in breast cancer cells that overexpress HER2 [30].
• Reactive lymphocytes responded to growth inhibitory TGF-beta by inducing p27Kip1 expression, with subsequent accumulation of cells in G0/G1 [31].
• NaBT decreased cyclin-dependent kinase CDK2 activity and induced p27 Kip1 expression; inhibition of GSK-3 rescued NaBT-inhibited CDK2 activity and blocked NaBT-induced p27 Kip1 expression in the nucleus but not in the cytoplasm [32].

Other interactions of CDKN1B

• In apoptotic cells, the C termini of the cdk inhibitors p21Cip1/Waf1 and p27Kip1 are truncated by specific cleavage [19].
• Sequestration of p27Kip1 protein by cyclin D1 in typical and blastic variants of mantle cell lymphoma (MCL): implications for pathogenesis [33].
• In addition, the putative loss of wild-type function of CDKN1B and ETV6 could indicate a synergistic effect of both genes in the pathogenesis of this leukemia case [2].
• These data suggest that pRb2/p130 and p27Kip1 may cooperate in regulating cellular proliferation, and both may be involved in a negative feedback regulatory loop with cyclin E [24].
• p27Kip1 is required for PTEN-induced G1 growth arrest [27].

Analytical, diagnostic and therapeutic context of CDKN1B

• In addition, a case-control study has shown that the 326T/G (V109G) polymorphism in CDKN1B is associated with advanced prostate cancer [1].
• Neither ETV6 nor CDKN1B was rearranged, as determined by FISH and Southern blotting; however, a small deletion encompassing the translocated CDKN1B allele was detected [34].
• Duplex PCR, with control primers known not to be deleted in the xenograft, was used to confirm that both the CDKN1B and ETV6 genes were homozygously deleted in the xenograft [35].
• Fluorescence in situ hybridization analysis of leukemia patients with del(12p) further refined the commonly deleted segment to 600 kb between ETV6 and D12S358, which apparently excludes CDKN1B [17].
• Western blot analysis of the nuclear and cytoplasmic fractions revealed a heterogenous localization pattern of p27Kip1 in AML [36].

References