Regulation of Cell Proliferation and Migration by Keratin19-Induced Nuclear Import of Early Growth Response-1 in Breast Cancer Cells

Ju, Ji-hyun; Yang, Wonseok; Lee, Kyung-min; Oh, Sunhwa; Nam, Kyoung Won; Shim, Sarah; Shin, Soon Young; Gye, Myung Chan; Chu, In-Sun; Shin, Incheol

doi:10.1158/1078-0432.ccr-12-3295

Cited by 62 publications

(69 citation statements)

References 38 publications

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“…We propose that mitogen stimulation of K17-expressing tumor cells results in posttranslational modifications of K17 that increase its nuclear targeting and binding of p27 KIP1 and CRM1, leading to p27 KIP1 export. Previous studies on other keratins reported their role in nuclear localization of Egr1 in breast cancer cells (41) and cytoplasmic retention of 14-3-3s in mouse keratinocytes (42). Therefore, the confirmation that K17 undergoes nuclear translocation casts light on the dynamic role of K17 that extends beyond its role in mechanical support, functioning as a nuclear shuttle for p27 KIP1 and potentially other tumor suppressors and nuclear proteins.…”

Section: Discussionmentioning

confidence: 76%

Keratin-17 Promotes p27KIP1 Nuclear Export and Degradation and Offers Potential Prognostic Utility

et al. 2015

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Keratins that are overexpressed selectively in human carcinomas may offer diagnostic and prognostic utility. In this study, we show that high expression of keratin-17 (K17) predicts poor outcome in patients with cervical cancer, at early or late stages of disease, surpassing in accuracy either tumor staging or loss of p27 KIP1 as a negative prognostic marker in this setting. We investigated the mechanistic basis for the biologic impact of K17 through loss-and gain-of-function experiments in human cervix, breast, and pancreatic cancer cells. Specifically, we determined that K17 functions as an oncoprotein by regulating the subcellular localization and degradation of p27 KIP1 . We found that K17 was released from intermediate filaments and translocated into the nucleus via a nuclear localization signal (NLS), specific among keratins, where it bound p27 KIP1 during G 1 phase of the cell cycle. p27 KIP1 lacks a nuclear export signal (NES) and requires an adaptor for CRM1 binding for nuclear export. In K17, we defined and validated a leucine-rich NES that mediated CRM1 binding for export. Cervical cancer cells expressing K17 mutations in its NLS or NES signals exhibited an increase in levels of nuclear p27 KIP1 , whereas cells expressing wild-type K17 exhibited a depletion in total endogenous p27 KIP1 . In clinical specimens of cervical cancer, we confirmed that the expressions of K17 and p27 KIP1 were inversely correlated, both across tumors and within individual tumors. Overall, our findings establish that K17 functions specially among keratins as an oncoprotein by controlling the ability of p27 KIP1 to influence cervical cancer pathogenesis. Cancer Res; 75(17); 3650-62. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 76%

Keratin-17 Promotes p27KIP1 Nuclear Export and Degradation and Offers Potential Prognostic Utility

et al. 2015

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“…36 However, it must be noted that complete silencing of KRT19 by shRNA leads to upregulation of cell proliferation by an increase in Akt activity via inhibition of Egr-1/PTEN, as we have reported very recently. 37 As indicated in Supplementary Figure 6, KRT19 exhibited a biphasic effect on cancer cell proliferation. The cell viability was dependent on KRT19/HER2 signaling at higher KRT19 concentration and it turned to be rather dependent on KRT19/Egr-1 signaling at very low/knockout levels of KRT19.…”

Section: Discussionmentioning

confidence: 91%

Cytokeratin19 induced by HER2/ERK binds and stabilizes HER2 on cell membranes

Lee

et al. 2014

Cell Death Differ

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Cytokeratin19 (KRT19) is widely used as a biomarker for the detection of disseminated tumors. Using an LC-MS/MS proteomics approach, we found that KRT19 was upregulated in HER2-overexpressing cells and tissues. KRT19 expression was induced by HER2-downstream ERK at the transcriptional level. Another HER2-downstream kinase, Akt, was found to phosphorylate KRT19 on Ser35 and induce membrane translocation of KRT19 and remodeling of KRT19 from filamentous to granulous form. KRT19 phosphorylated by Akt could bind HER2 on the plasma membrane and stabilized HER2 via inhibition of proteasome-mediated degradation of HER2. Silencing of KRT19 by shRNA resulted in increased ubiquitination and destabilization of HER2. Moreover, treatment of KRT19 antibody resulted in downregulation of HER2 and reduced cell viability. These data provide a new rationale for targeting HER2-positive breast cancers.

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“…Keratins have been implicated in the modulation of Akt and mTOR signaling pathways through direct physical interaction with the adapter protein 14-3-3σ stratifin) [41], AMP-activated protein kinase (AMPK) [42] and Akt/PKB [43, 44], or via transcriptional regulation of the effector genes in the pathway [14, 45]. Previous studies on the regulation of nociceptive mechanisms show that sensory axonal protein synthesis also occurs under the control of the mTOR signaling pathway [47–49].…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling in pachyonychia congenita skin

Cao¹,

Hickerson²,

Seegmiller³

et al. 2015

Journal of Dermatological Science

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Background Pachyonychia congenita (PC) is a skin disorder resulting from mutations in keratin (K) proteins including K6a, K6b, K16, and K17. One of the major symptoms is painful plantar keratoderma. The pathogenic sequelae resulting from the keratin mutations remain unclear. Objective To better understand PC pathogenesis. Methods RNA profiling was performed on biopsies taken from PC-involved and uninvolved plantar skin of seven genotyped PC patients (two K6a, one K6b, three K16, and one K17) as well as from control volunteers. Protein profiling was generated from tape-stripping samples. Results A comparison of PC-involved skin biopsies to adjacent uninvolved plantar skin identified 112 differentially-expressed mRNAs common to patient groups harboring K6 (i.e., both K6a and K6b) and K16 mutations. Among these mRNAs, 25 encode structural proteins including keratins, small proline-rich and late cornified envelope proteins, 20 are related to metabolism and 16 encode proteases, peptidases, and their inhibitors including kallikrein-related peptidases (KLKs), and serine protease inhibitors (SERPINs). mRNAs were also identified to be differentially expressed only in K6 (81) or K16 (141) patient samples. Furthermore, 13 mRNAs were identified that may be involved in pain including nociception and neuropathy. Protein profiling, comparing three K6a plantar tape-stripping samples to non-PC controls, showed changes in the PC corneocytes similar, but not identical, to the mRNA analysis. Conclusion Many differentially-expressed genes identified in PC-involved skin encode components critical for skin barrier homeostasis including keratinocyte proliferation, differentiation, cornification, and desquamation. The profiling data provide a foundation for unraveling the pathogenesis of PC and identifying targets for developing effective PC therapeutics.

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Regulation of Cell Proliferation and Migration by Keratin19-Induced Nuclear Import of Early Growth Response-1 in Breast Cancer Cells

Cited by 62 publications

References 38 publications

Keratin-17 Promotes p27KIP1 Nuclear Export and Degradation and Offers Potential Prognostic Utility

Keratin-17 Promotes p27KIP1 Nuclear Export and Degradation and Offers Potential Prognostic Utility

Cytokeratin19 induced by HER2/ERK binds and stabilizes HER2 on cell membranes

Gene expression profiling in pachyonychia congenita skin

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