NKX3.1 Is Regulated by Protein Kinase CK2 in Prostate Tumor Cells

Li, Xiang; Guan, Bin; Maghami, S A Ghaem; Bieberich, Charles J.

doi:10.1128/mcb.26.8.3008-3017.2006

Cited by 43 publications

(56 citation statements)

References 54 publications

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“…Amino acid residues 81 to 97 comprise a Pro-Glu-Ser-Thr-rich sequence that mediates NKX3.1 turnover by polyubiquitination (23). Protein kinase CK2 phosphorylation at threonine residues within this domain protects NKX3.1 from proteasomal degradation (23).…”

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confidence: 99%

Proline-mediated Proteasomal Degradation of the Prostate-specific Tumor Suppressor NKX3.1

Rao

Guan

Mutton

et al. 2012

Journal of Biological Chemistry

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Background:The prostate-specific tumor suppressor NKX3.1 is targeted for proteasomal degradation. Results: A proline-dependent C-terminal 21 amino acid portable degron regulates NKX3.1 ubiquitin-independent degradation in prostate cancer cells. Conclusion: NKX3.1 proteasomal degradation is mediated by both ubiquitin-dependent and -independent pathways. Significance: Understanding mechanisms regulating NKX3.1 turnover provides opportunities to develop tumor suppressor restoration therapies in prostate cancer.

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confidence: 99%

Proline-mediated Proteasomal Degradation of the Prostate-specific Tumor Suppressor NKX3.1

Rao

Guan

Mutton

et al. 2012

Journal of Biological Chemistry

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“…FLAG-NKX3.1 was approximately 5-fold in excess over endogenous NKX3.1 ( Supplementary Figure S1A) but localized primarily to cell nuclei ( Supplementary Figure S1B). The proteasome inhibitor MG132 was added 4 hours prior to lysate preparation in order to slow the rapid clearance via the ubiquitin-proteasome pathway to which NKX3.1 is normally subjected 34, 35 . Cell lysate was absorbed to anti-FLAG M2 resin, and specifically retained proteins were eluted with FLAG peptide.…”

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confidence: 99%

Systems analysis of the prostate tumor suppressor NKX3.1 supports roles in DNA repair and luminal cell differentiation

Yang

Chung²,

et al. 2014

F1000Res

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NKX3.1 is a homeobox transcription factor whose function as a prostate tumor suppressor remains insufficiently understood because neither the transcriptional program governed by NKX3.1, nor its interacting proteins have been fully revealed. Using affinity purification and mass spectrometry, we have established an extensive NKX3.1 interactome which contains the DNA repair proteins Ku70, Ku80, and PARP, thus providing a molecular underpinning to previous reports implicating NKX3.1 in DNA repair. Transcriptomic profiling of NKX3.1-negative prostate epithelial cells acutely expressing NKX3.1 revealed a rapid and complex response that is a near mirror image of the gene expression signature of human prostatic intraepithelial neoplasia (PIN). Pathway and network analyses suggested that NKX3.1 actuates a cellular reprogramming toward luminal cell differentiation characterized by suppression of pro-oncogenic c-MYC and interferon-STAT signaling and activation of tumor suppressor pathways. Consistently, ectopic expression of NKX3.1 conferred a growth arrest depending on TNFα and JNK signaling. We propose that the tumor suppressor function of NKX3.1 entails a transcriptional program that maintains the differentiation state of secretory luminal cells and that disruption of NKX3.1 contributes to prostate tumorigenesis by permitting luminal cell de-differentiation potentially augmented by defects in DNA repair.

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“…The double transfection method for siRNA using Lipofectamine 2000 was as described (17). siRNA was synthesized at the University of Maryland, Baltimore, Biopolymer Core Facility.…”

Section: Methodsmentioning

confidence: 99%

“…In vitro reactions were carried out at 37°C for 60 -90 min in a 10-l volume. In vivo ubiquitination assays were performed as described (17).…”

Section: Methodsmentioning

confidence: 99%

“…NKX3.1 is known to be phosphorylated by protein kinase C, and this modification regulates DNA binding activity (16). We previously reported that the stability of NKX3.1 protein is regulated by protein kinase CK2 in LNCaP cells, and CK2 phosphorylation prevents ubiquitin-mediated NKX3.1 degradation by the 26S proteasome (17). Ubiquitin is an 8-kDa small-molecule modifier that can be covalently attached to lysine residues of a substrate protein.…”

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Ubiquitination by TOPORS Regulates the Prostate Tumor Suppressor NKX3.1

Guan

Pungaliya

et al. 2008

Journal of Biological Chemistry

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The NKX3.1 gene located at 8p21.2 encodes a homeodomaincontaining transcription factor that acts as a haploinsufficient tumor suppressor in prostate cancer. Diminished protein expression of NKX3.1 has been observed in prostate cancer precursors and carcinomas. TOPORS is a ubiquitously expressed E3 ubiquitin ligase that can ubiquitinate tumor suppressor p53. Here we report interaction between NKX3.1 and TOPORS. NKX3.1 can be ubiquitinated by TOPORS in vitro and in vivo, and overexpression of TOPORS leads to NKX3.1 proteasomal degradation in prostate cancer cells. Conversely, small interfering RNA-mediated knockdown of TOPORS leads to an increased steady-state level and prolonged half-life of NKX3.1. These data establish TOPORS as a negative regulator of NKX3.1 and implicate TOPORS in prostate cancer progression.Prostate cancer is the second leading cause of cancer deaths and the most frequently diagnosed malignancy in American men (1). Prostate carcinomas are considered to arise from cancer precursors including prostatic intraepithelial neoplasia (PIN) 2 and proliferative inflammatory atrophy (2). Molecular alterations, including hereditary and somatic gene mutations, gene deletions, gene amplification, chromosomal rearrangements, as well as epigenetic changes, have been implicated in prostate cancer initiation and progression (3).The NK class homeobox gene NKX3.1 has been studied extensively over the past decade for its roles in prostate development and carcinogenesis (4). The expression of the murine Nkx3.1 gene is androgen-dependent and is restricted largely to prostate epithelial cells in adults (5-7). Deletion of Nkx3.1 by gene targeting leads to prostate ductal morphological defects, as well as prostatic dysplasia and hyperplasia that resembles human PIN (8 -10). Interestingly, heterozygous Nkx3.1 mice also develop hyperplasia and PIN-like lesions (8). The human NKX3.1 gene maps to 8p21.2 within a region where loss of heterozygosity occurs in PIN and is common in prostate carcinomas; however, no mutations have been found in the coding region of the NKX3.1 allele remaining (11,12). In light of these observations, NKX3.1 has been proposed to function as a haploinsufficient tumor suppressor. In support of a dose-dependent growth regulatory function of NKX3.1, reduced but not complete loss of NKX3.1 protein expression is now well documented in most human prostate cancer samples in a manner inversely correlated with Gleason score (13) and also with disease progression (14). Diminished NKX3.1 expression is thought to be an early event in prostate carcinogenesis, and reduced NKX3.1 immunostaining was observed in most proliferative inflammatory atrophy and PIN lesions analyzed (13). The diminished NKX3.1 expression may be partly attributed to selective CpG methylation of the NKX3.1 promoter in some prostate cancer cases (15). Nevertheless, quantitative analyses of mRNA and protein levels of NKX3.1 in prostate carcinoma lesions revealed a lack of concordance between mRNA and protein levels (13). In particular, decre...

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NKX3.1 Is Regulated by Protein Kinase CK2 in Prostate Tumor Cells

Cited by 43 publications

References 54 publications

Proline-mediated Proteasomal Degradation of the Prostate-specific Tumor Suppressor NKX3.1

Proline-mediated Proteasomal Degradation of the Prostate-specific Tumor Suppressor NKX3.1

Systems analysis of the prostate tumor suppressor NKX3.1 supports roles in DNA repair and luminal cell differentiation

Ubiquitination by TOPORS Regulates the Prostate Tumor Suppressor NKX3.1

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