A translationally regulated Tousled kinase phosphorylates histone H3 and confers radioresistance when overexpressed

Li, Yuan; DeFatta, Robert J.; Anthony, Charles; Sunavala, Gulshan; Benedetti, Arrigo De

doi:10.1038/sj.onc.1204147

Cited by 90 publications

(167 citation statements)

References 35 publications

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“…TLK1 and TLK1B are known to phosphorylate the same substrates identified to date, namely, histone H3, antisilencing factor 1, and Rad9 (Li et al, 2001;Sillje and Nigg, 2001;Sunavala-Dossabhoy et al, 2003;Sunavala-Dossabhoy and De Benedetti, 2009). We have shown that expression of TLK1B in mouse epithelial cells does not induce oncogenic transformation, but it does increase the cell's ability to overcome radiation injury (Li et al, 2001;SunavalaDossabhoy et al, 2003;Sunavala-Dossabhoy et al, 2005). This holds true for irradiated normal rat salivary acinar and ductal cells transduced with exogenous TLK1B as well (Palaniyandi et al, 2011;Sunavala-Dossabhoy et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…A spliced variant of TLK1, TLK1B, is identical to full-length protein except from the loss of 237 N-terminal amino acids (Li et al, 2001). TLK1 and TLK1B are known to phosphorylate the same substrates identified to date, namely, histone H3, antisilencing factor 1, and Rad9 (Li et al, 2001;Sillje and Nigg, 2001;Sunavala-Dossabhoy et al, 2003;Sunavala-Dossabhoy and De Benedetti, 2009). We have shown that expression of TLK1B in mouse epithelial cells does not induce oncogenic transformation, but it does increase the cell's ability to overcome radiation injury (Li et al, 2001;SunavalaDossabhoy et al, 2003;Sunavala-Dossabhoy et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Tousled-like kinase 1B and its larger variant TLK1 are cellular proteins that play a role in cell cycle arrest, chromatin remodeling, and DNA repair (Groth et al, 2003;Sunavala-Dossabhoy et al, 2005;Canfield et al, 2009;Sunavala-Dossabhoy and De Bendetti, 2009;De Benedetti, 2010). Their role in facilitating DNA repair is emphasized by observations that overexpression of the protein protects cells against death by radiation (Li et al, 2001;Sunavala-Dossabhoy et al, 2005), whereas suppression of its kinase activity or knockdown of the protein enhances the cell's susceptibility to DNA damage-induced cell death (SunavalaDossabhoy et al, 2003;Takayama et al, 2010). We have shown before that exogenous TLK1B in rat submandibular salivary glands effectively attenuates xerostomia associated with a single large-dose radiation (Palaniyandi et al, 2011;SunavalaDossabhoy et al, 2012).…”

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confidence: 99%

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Recombinant AAV9-TLK1B Administration Ameliorates Fractionated Radiation-Induced Xerostomia

Shanmugam

Dayton²,

Palaniyandi³

et al. 2013

Human Gene Therapy

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Salivary glands are highly susceptible to radiation, and patients with head and neck cancer treated with radiotherapy invariably suffer from its distressing side effect, salivary hypofunction. The reduction in saliva disrupts oral functions, and significantly impairs oral health. Previously, we demonstrated that adenoviralmediated expression of Tousled-like kinase 1B (TLK1B) in rat submandibular glands preserves salivary function after single-dose ionizing radiation. To achieve long-term transgene expression for protection of salivary gland function against fractionated radiation, this study examines the usefulness of recombinant adeno-associated viral vector for TLK1B delivery. Lactated Ringers or AAV2/9 with either TLK1B or GFP expression cassette were retroductally delivered to rat submandibular salivary glands (10 11 vg/gland), and animals were exposed, or not, to 20 Gy in eight fractions of 2.5 Gy/day. AAV2/9 transduced predominantly the ductal cells, including the convoluted granular tubules of the submandibular glands. Transgene expression after virus delivery could be detected within 5 weeks, and stable gene expression was observed till the end of study. Pilocarpine-stimulated saliva output measured at 8 weeks after completion of radiation demonstrated >10-fold reduction in salivary flow in saline-and AAV2/9-GFP-treated animals compared with the respective nonirradiated groups (90.8% and 92.5% reduction in salivary flow, respectively). Importantly, there was no decrease in stimulated salivary output after irradiation in animals that were pretreated with AAV2/9-TLK1B (121.5% increase in salivary flow; p < 0.01). Salivary gland histology was better preserved after irradiation in TLK1B-treated group, though not significantly, compared with control groups. Single preemptive delivery of AAV2/9-TLK1B averts salivary dysfunction resulting from fractionated radiation. Although AAV2/9 transduces mostly the ductal cells of the gland, their protection against radiation assists in preserving submandibular gland function. AAV2/9-TLK1B treatment could prove beneficial in attenuating xerostomia in patients with head and neck cancer undergoing radiotherapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Recombinant AAV9-TLK1B Administration Ameliorates Fractionated Radiation-Induced Xerostomia

Shanmugam

Dayton²,

Palaniyandi³

et al. 2013

Human Gene Therapy

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“…[15][16][17][18] A spliced variant of the human TLK1, TLK1B, was identified in our laboratory during a library screening of transcripts dependent on eukaryotic translation initiation factor 4E (eIF4E). 19 TLK1B mRNA has a long, structured 5¢ UTR (Figure 1), which when deleted relieves its dependence on increased eIF4E and allows its translation in normal cells. 19 The splice variant, TLK1B, is identical to the full-length TLK1 except for the exclusion of 237 N-terminal amino acids.…”

Section: Introductionmentioning

confidence: 99%

Adenoviral delivery of Tousled kinase for the protection of salivary glands against ionizing radiation damage

Palaniyandi

Odaka

et al. 2010

Gene Ther

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Oral complications of salivary hypofunction often afflict cancer patients undergoing radiotherapy for head and neck cancers. Dry mouth or xerostomia is an undesirable consequence of radiotherapy that compromises normal oral functions in addition to causing odynophagia and increasing the patient's risk of oral infections and dental caries. Radiation-induced xerostomia is irreversible, and palliative measures to provide symptomatic relief remain the mainstay of treatment. Previously, we identified a splice variant of a cellular kinase, Tousled-like kinase 1B (TLK1B), which when overexpressed protects normal epithelial cells against ionizing radiation (IR)-induced cell death. To address the need to protect salivary glands in patients undergoing regional radiotherapy, we investigated whether preemptive expression of TLK1B in salivary glands protects against IR. In stably-derived salivary cell lines in vitro, TLK1B expression increased cell survival after IR. Cells expressing exogenous TLK1B were less radiosensitive (A5-TLK1B, a/b¼0.67 Gy; ParC5-TLK1B, a/b¼4.3 Gy) compared to control cells (A5-BK, a/b¼1.7 Gy; ParC5-BK, a/b¼32.7 Gy). Using a recombinant adenovirus serotype 5 viral vector for TLK1B gene transfer into rat submandibular salivary glands in vivo, we demonstrated that TLK1B protects the saliva-secreting acinar cells and better preserves salivary gland function against IR relative to control glands. After a single fraction of 16 Gy, the decline in salivary function at 8 weeks was less pronounced in TLK1B-treated animals (40%) as compared to saline-treated controls (67%). Histopathological analysis demonstrated increase in acinar atrophy, decrease in acinar cell number, and increase in inflammatory infiltrate and fibrosis in irradiated control tissues relative to TLK1B-treated glands. These results show the radioprotective benefits of TLK1B and implicate its usefulness in the management of regional radiotherapy-induced xerostomia.

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TLK1‐mediated MK5‐S354 phosphorylation drives prostate cancer cell motility and may signify distinct pathologies

et al. 2022

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Metastases account for the majority of prostate cancer (PCa) deaths, and targeting them is a major goal of systemic therapy. We identified a novel interaction between two kinases: tousled-like kinase 1 (TLK1) and MAP kinase-activated protein kinase 5 (MK5) that promotes PCa spread. In PCa progression, TLK1-MK5 signalling appears to increase following antiandrogen treatment and in metastatic castration-resistant prostate cancer (mCRPC) patients. Determinations of motility rates (2D and 3D) of different TLK1-and MK5-perturbed cells, including knockout (KO) and knockdown (KD), as well as the use of specific inhibitors, showed the importance of these two proteins for in vitro dissemination. We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells. Expression of MK5-S354A or kinase-dead MK5 in MK5-depleted mouse embryonic fibroblast (MEF) cells failed to restore their motility compared with that of wild-type (WT) MK5-rescued MK5 À/À MEF cells. A pMK5-S354 antiserum was used to establish this site as an authentic TLK1 target in androgen-sensitive human prostate adenocarcinoma (LNCaP) cells, and was used in immunohistochemistry (IHC) studies of age-related PCa sections from TRAMP (transgenic adenocarcinoma of the mouse prostate) mice and to probe a human tissue microarray (TMA), which revealed pMK5-S354 level is correlated with disease progression (Gleason score and nodal metastases). In addition, The Cancer Genome Atlas (TCGA) analyses of PCa expression and genome-wide association study (GWAS) relations identify TLK1 and MK5 as potential drivers of advanced PCa and as markers of mCRPC. Our work suggests that TLK1-MK5 signalling is functionally involved in driving PCa cell motility and clinical features of aggressiveness; hence, disruption of this axis may inhibit the metastatic spread of PCa.

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A translationally regulated Tousled kinase phosphorylates histone H3 and confers radioresistance when overexpressed

Cited by 90 publications

References 35 publications

Recombinant AAV9-TLK1B Administration Ameliorates Fractionated Radiation-Induced Xerostomia

Recombinant AAV9-TLK1B Administration Ameliorates Fractionated Radiation-Induced Xerostomia

Adenoviral delivery of Tousled kinase for the protection of salivary glands against ionizing radiation damage

TLK1‐mediated MK5‐S354 phosphorylation drives prostate cancer cell motility and may signify distinct pathologies

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