Constitutively Active K-cyclin/cdk6 Kinase in Kaposi Sarcoma–Associated Herpesvirus–Infected Cells

Dross, Rukiyah Van; Yao, Shanshan; Asad, Shaheena; Westlake, Grant; Mays, Deborah J.; Barquero, Laura A.; Duell, Stephanie; Pietenpol, Jennifer A.; Browning, Philip J.

doi:10.1093/jnci/dji113

Cited by 31 publications

(25 citation statements)

References 44 publications

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“…As shown in Fig. 3B, p21 Cip1 and K cyclin were in complex in BC-3 cells, confirming our results from transfected cells and in agreement with recently published data (39). JOK-1 is a KSHV-negative leukemia cell line, which served as a negative control.…”

Section: Initially We Tested If P21supporting

confidence: 93%

Phosphorylation of the Cyclin-Dependent Kinase Inhibitor p21^Cip1 on Serine 130 Is Essential for Viral Cyclin-Mediated Bypass of a p21^Cip1-Imposed G₁ Arrest

Järviluoma

Child

Sarek

et al. 2006

Molecular and Cellular Biology

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Cip1 acts in a manner similar to that of p27 Kip1 , we have investigated the subversion of a p21 Cip1 -induced G 1 arrest by K cyclin. Here, we show that p21Cip1 is associated with K cyclin both in overexpression models and in primary effusion lymphoma cells and is a substrate of the K cyclin/cdk6 complex, resulting in phosphorylation of p21Cip1 on serine 130. This phosphoform of p21Cip1 appeared unable to associate with cdk2 in vivo. We further demonstrate that phosphorylation on serine 130 is essential for K cyclin-mediated release of a p21Cip1 -imposed G 1 arrest. Moreover, we show that under physiological conditions of cell cycle arrest due to elevated levels of p21 Cip1 resulting from oxidative stress, K cyclin expression enabled S-phase entry and was associated with p21Cip1 phosphorylation and partial restoration of cdk2 kinase activity. Thus, expression of the viral cyclin enables cells to subvert the cell cycle inhibitory function of p21Cip1 by promoting cdk6-dependent phosphorylation of this antiproliferative protein.

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Section: Initially We Tested If P21supporting

confidence: 93%

Phosphorylation of the Cyclin-Dependent Kinase Inhibitor p21^Cip1 on Serine 130 Is Essential for Viral Cyclin-Mediated Bypass of a p21^Cip1-Imposed G₁ Arrest

Järviluoma

Child

Sarek

et al. 2006

Molecular and Cellular Biology

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“…More than 90% of IPF patients were found to be PCR positive for herpesviruses in the lungs, whereas two other viruses reactivated by immunosuppression were not detected (20). As with misfolded proteins, herpesvirus infections can activate the UPR because of viral proteins produced and passaged through the ER (6,10,29). Remarkably, however, the normal consequences of UPR activation are modified to benefit the virus.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection

Lawson

Crossno²,

Polosukhin³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

380

354

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Recent evidence suggests that dysfunctional type II alveolar epithelial cells (AECs) contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Based on the hypothesis that disease-causing mutations in surfactant protein C ( SFTPC) provide an important paradigm for studying IPF, we investigated a potential mechanism of AEC dysfunction suggested to result from mutant SFTPC expression: induction of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). We evaluated biopsies from 23 IPF patients (including 3 family members with L188Q SFTPC mutations, 10 individuals with familial interstitial pneumonia without SFTPC mutations, and 10 individuals with sporadic IPF) and sections from 10 control lungs. After demonstrating UPR activation in cultured A549 cells expressing mutant SFTPC, we identified prominent expression of UPR markers in AECs in the lungs of patients with SFTPC mutation-associated fibrosis. In individuals with familial interstitial pneumonia without SFTPC mutations and patients with sporadic IPF, we also found UPR activation selectively in AECs lining areas of fibrotic remodeling. Because herpesviruses are found frequently in IPF lungs and can induce ER stress, we investigated expression of viral proteins in lung biopsies. Herpesvirus protein expression was found in AECs from 15/23 IPF patients and colocalized with UPR markers in AECs from these patients. ER stress and UPR activation are found in the alveolar epithelium in patients with IPF and could contribute to disease progression. Activation of these pathways may result from altered surfactant protein processing or chronic herpesvirus infection.

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“…In addition, recent work has linked the activation of CDK1 adjacent to the cell membranes in the promotion of cell movement during interphase (34). In contrast, K-cyclin expression and associated kinase activityisconstantthroughoutthecellcycle,andK-cyclin⅐CDK6complexesare present both in the nucleus and in the cytoplasm in KSHV-transformed cells (71). Furthermore, K-cyclin-activated kinases are known to evade regulatory loops that restrain the activity of cellular cyclin⅐CDKs in response to extracellular signaling cues (3).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Microfilament Organization by Kaposi Sarcoma-associated Herpes Virus-cyclin·CDK6 Phosphorylation of Caldesmon

Cuomo

Knebel

Platt

et al. 2005

Journal of Biological Chemistry

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Kaposi sarcoma-associated herpes virus (KSHV) encodes a D-like cyclin (K-cyclin) that is thought to contribute to the viral oncogenicity. K-cyclin activates cellular cyclin-dependent kinases (CDK) 4 and 6, generating enzymes with a substrate selectivity deviant from CDK4 and CDK6 activated by D-type cyclins, suggesting different biochemical and biological functions. Here we report the identification of the actin-and calmodulin-binding protein caldesmon (CALD1) as a novel K-cyclin⅐CDK substrate, which is not phosphorylated by D⅐CDK. CALD1 plays a central role in the regulation of microfilament organization, consequently controlling cell shape, adhesion, cytokinesis and motility. K-cyclin⅐CDK6 specifically phosphorylates four Ser/Thr sites in the human CALD1 carboxyl terminus, abolishing CALD1 binding to its effector protein, actin, and its regulator protein, calmodulin. CALD1 is hyperphosphorylated in cells following K-cyclin expression and in KSHV-transformed lymphoma cells. Moreover, expression of exogenous K-cyclin results in microfilament loss and changes in cell morphology; both effects are reliant on CDK catalysis and can be reversed by the expression of a phosphorylation defective CALD1. Together, these data strongly suggest that K-cyclin expression modulates the activity of caldesmon and through this the microfilament functions in cells. These results establish a novel link between KSHV infection and the regulation of the actin cytoskeleton.Nearly all cellular responses are controlled through protein phosphorylation and the protein kinases catalyzing this process represent the largest single family of enzymes (1). The choice of substrates determines the selectivity of the kinase action and its cellular impact. Therefore, the nature of the substrates of a kinase can provide important clues as to its physiological role and function (2).Recently, several oncogenic gamma herpesviruses have been described to contain within their genome a cyclin-like activator for cyclin-dependent kinases (CDKs) 3 (3). The Kaposi sarcoma herpes virus (KSHV) or human herpes virus 8 (HHV8), a human tumor virus associated with the development of Kaposi sarcoma and several lymphoid malignancies in immunocompromised individuals (4 -6), encodes a cyclin (K-cyclin) that is thought to have descended from cellular D-type cyclins based on co-linearity and sequence identity. Strong evidence from transgenic mouse models suggests that K-cyclin contributes significantly to the oncogenic process elicited by this virus (7,8). D-type cyclins are recognized for their involvement in human oncogenesis (9) and K-cyclin shares their ability to activate the closely related cellular CDK4 and CDK6 and hence phosphorylate and inactivate the retinoblastoma tumor suppressor protein (Rb) (10).In addition to Rb, K-cyclin⅐CDK complexes can phosphorylate proteins that are not substrates for those CDKs when activated by cellular cyclin D. These include the CDK inhibitor p27 KIP , which is normally phosphorylated by cyclin E⅐CDK2, targeting it for degradation b...

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Constitutively Active K-cyclin/cdk6 Kinase in Kaposi Sarcoma–Associated Herpesvirus–Infected Cells

Abstract: The constitutive activation of K-cyclin/cdk complexes in KSHV-infected cells appears to result from the extended half-life of K-cyclin and may explain its role in Kaposi sarcoma.

Cited by 31 publications

References 44 publications

Phosphorylation of the Cyclin-Dependent Kinase Inhibitor p21^Cip1 on Serine 130 Is Essential for Viral Cyclin-Mediated Bypass of a p21^Cip1-Imposed G₁ Arrest

Phosphorylation of the Cyclin-Dependent Kinase Inhibitor p21^Cip1 on Serine 130 Is Essential for Viral Cyclin-Mediated Bypass of a p21^Cip1-Imposed G₁ Arrest

Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection

Regulation of Microfilament Organization by Kaposi Sarcoma-associated Herpes Virus-cyclin·CDK6 Phosphorylation of Caldesmon

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Constitutively Active K-cyclin/cdk6 Kinase in Kaposi Sarcoma–Associated Herpesvirus–Infected Cells

Abstract: The constitutive activation of K-cyclin/cdk complexes in KSHV-infected cells appears to result from the extended half-life of K-cyclin and may explain its role in Kaposi sarcoma.

Cited by 31 publications

References 44 publications

Phosphorylation of the Cyclin-Dependent Kinase Inhibitor p21Cip1 on Serine 130 Is Essential for Viral Cyclin-Mediated Bypass of a p21Cip1-Imposed G1 Arrest

Phosphorylation of the Cyclin-Dependent Kinase Inhibitor p21Cip1 on Serine 130 Is Essential for Viral Cyclin-Mediated Bypass of a p21Cip1-Imposed G1 Arrest

Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection

Regulation of Microfilament Organization by Kaposi Sarcoma-associated Herpes Virus-cyclin·CDK6 Phosphorylation of Caldesmon

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Phosphorylation of the Cyclin-Dependent Kinase Inhibitor p21^Cip1 on Serine 130 Is Essential for Viral Cyclin-Mediated Bypass of a p21^Cip1-Imposed G₁ Arrest

Phosphorylation of the Cyclin-Dependent Kinase Inhibitor p21^Cip1 on Serine 130 Is Essential for Viral Cyclin-Mediated Bypass of a p21^Cip1-Imposed G₁ Arrest