Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein

Lan, Ke; Verma, Subhash C.; Murakami, Masanao; Bajaj, Bharat; Kaul, Rajeev; Robertson, Erle S.

doi:10.1073/pnas.0703508104

Cited by 54 publications

(66 citation statements)

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“…Thus, we validated the fact that LANA upregulates Hey1 through prevention of its degradation. In our previous work, we demonstrated that LANA stabilized Notch ICD, facilitating cell survival (30). Here, we have demonstrated that LANA hijacks the Notch signaling pathway, leading to pathologic angiogenesis in Kaposi sarcoma, by targeting Hey1.…”

Section: Discussionmentioning

confidence: 99%

“…Kaposi sarcoma is a typical angioproliferative neoplasm characterized by large amounts of neoangiogenesis throughout its pathologic process (3,4). It is commonly agreed that Notch signaling plays critical roles in Kaposi sarcoma tumorigenesis (8,(15)(16)(17)(18)30). However, whether it is involved in Kaposi sarcoma angiogenesis is far from fully understood (9,17).…”

Section: Discussionmentioning

confidence: 99%

“…We reported previously that KSHV LANA stabilizes ICN and contributes to cell proliferation (30). Herein, we chose to identify the major component of KSHV that manipulates Hey1, and to elucidate the mechanism further.…”

Section: Lana Was the Major Component That Upregulated Hey1 Expressiomentioning

confidence: 99%

“…The pA3F-LANA, which encodes the full length of LANA-1, has been described previously (30). Human Hey1 was amplified from a 293T cell cDNA library and cloned into pCDNA3.1-HA (Invitrogen), pCDNA3.1-Myc-His, and lentivector pCDH-CMV-IRES-Blast plasmid, respectively.…”

Section: Plasmids Shrna and Transfectionmentioning

confidence: 99%

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Latency-Associated Nuclear Antigen of Kaposi Sarcoma–Associated Herpesvirus Promotes Angiogenesis through Targeting Notch Signaling Effector Hey1

Wang

Tian

et al. 2014

Cancer Research

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Notch signaling has been implicated in the pathogenesis of Kaposi sarcoma. Kaposi sarcoma is an angioproliferative neoplasm that originates from Kaposi sarcoma-associated herpesvirus (KSHV) infection. Previously, we showed that the KSHV LANA protein can stabilize intracellular Notch in KSHV-infected tumor cells and promote cell proliferation. However, whether Notch signaling functions in pathologic angiogenesis of Kaposi sarcoma remains largely unknown. Hey1, an essential downstream effector of the Notch signaling pathway, has been demonstrated to play a fundamental role in vascular development. In the present study, we performed whole transcriptome, paired-end sequencing on three patient-matched clinical Kaposi sarcoma specimens and their corresponding adjacent stroma samples, with an average depth of 42 million reads per sample. Dll4, Hey1, and HeyL displayed significant upregulation in Kaposi sarcoma. Further verification based on immunohistochemistry analysis demonstrated that Hey1 was indeed highly expressed in Kaposi sarcoma lesions. Using the Matrigel plug assay, we showed that downregulation of Hey1 and g-secretase inhibitor treatment caused dramatic reduction in the formation of new blood vessels in mice. Interestingly, LANA was responsible for the elevated level of Hey1 through inhibition of its degradation. Importantly, Hey1 stabilized by LANA promoted the neoplastic vasculature. Taken together, our data suggest that hijacking of the proangiogenic property of Hey1 by LANA is an important strategy utilized by KSHV to achieve pathologic angiogenesis and that Hey1 is a potential therapeutic target in Kaposi sarcoma. Cancer Res; 74(7); 2026-37. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Lana Was the Major Component That Upregulated Hey1 Expressiomentioning

confidence: 99%

Section: Plasmids Shrna and Transfectionmentioning

confidence: 99%

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Latency-Associated Nuclear Antigen of Kaposi Sarcoma–Associated Herpesvirus Promotes Angiogenesis through Targeting Notch Signaling Effector Hey1

Wang

Tian

et al. 2014

Cancer Research

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“…3 LANA can stabilize activated forms of Notch receptor, a pathway with diverse functions, including transformation and regulation of the vascular system. 4 vFLIP activates the nuclear factor-B (NF-B) pathway, induces spindle cell phenotype, and induces transformation in vitro and in vivo. 5 Lytic phase viral proteins also regulate major signaling pathways, which may lead to transformation, regulate self-renewal, and induce angiogenesis and inflammation.…”

Section: Introductionmentioning

confidence: 99%

KSHV-induced notch components render endothelial and mural cell characteristics and cell survival

Liu¹,

Li²,

Tulpule³

et al. 2010

Blood

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Kaposi sarcoma–associated herpesvirus (KSHV) infection is essential to the development of Kaposi sarcoma (KS). Notch signaling is also known to play a pivotal role in KS cell survival and lytic phase entrance of KSHV. In the current study, we sought to determine whether KSHV regulates Notch components. KSHV-infected lymphatic endothelial cells showed induction of receptors Notch3 and Notch4, Notch ligands Dll4 and Jagged1, and activated Notch receptors in contrast to uninfected lymphatic endothelial cells. In addition, KSHV induced the expression of endothelial precursor cell marker (CD133) and mural cell markers (calponin, desmin, and smooth muscle alpha actin), suggesting dedifferentiation and trans-differentiation. Overexpression of latency proteins (LANA, vFLIP) and lytic phase proteins (RTA, vGPCR, viral interleukin-6) further supported the direct regulatory capacity of KSHV viral proteins to induce Notch receptors (Notch2, Notch3), ligands (Dll1, Dll4, Jagged1), downstream targets (Hey, Hes), and endothelial precursor CD133. Targeting Notch pathway with γ-secretase inhibitor and a decoy protein in the form of soluble Dll4 inhibited growth of KSHV-transformed endothelial cell line. Soluble Dll4 was also highly active in vivo against KS tumor xenograft. It inhibited tumor cell growth, induced tumor cell death, and reduced vessel perfusion. Soluble Dll4 is thus a candidate for clinical investigation.

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A Review of the Epidemiology and the Mechanisms Underlying KSHV ‐induced Malignancies

Alkharsah

Schulz

Weidner-Glunde

2009

Encyclopedia of Life Sciences

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Kaposi's sarcoma herpesvirus (KSHV), also called human herpesvirus‐8 (HHV‐8), is believed to be the infectious causative agent of Kaposi's sarcoma and two other rare acquired immune deficiency syndrome (AIDS)‐associated neoplastic diseases. KSHV is relatively frequent in some countries of the Mediterranean area, and quite common in sub‐Saharan and South Africa, but rare in most other parts of the world. The virus is transmitted through sexual contact among adults. However, in endemic countries, the mode of transmission is most probably via behavioural practices using saliva from mother to child and between siblings. KSHV persists in infected cells in a latent episomal form expressing only a small number of genes to escape immune surveillance. These genes play a significant role in viral persistence and development of malignancy. A small number of KSHV‐infected cells undergo spontaneous lytic reactivation to ensure the production of new virions and provide inflammatory cytokines that participate in development of cancer. Key concepts: KSHV is a γ2‐herpesvirus (Rhadinovirus) that causes Kaposi sarcoma, Primary effusion lymphoma and Multicentric Castleman's disease mainly in immunocompromised individuals, e.g. AIDS patients. Similarly to the other herpesviruses KSHV has two phases of replication, latent and lytic. In malignancies, the virus is detected mainly in latent state, where only few proteins are expressed. Small number of infected cells undergo spontaneous lytic reactivation producing both, new virions for infecting new cells and inflammatory cytokines, which contribute to tumourigenesis through a paracrine mechanism. KSHV expresses several genes that play a role in inhibition of apoptosis (vFLIP, vBCL2), progression of cell cycle (vCYC, LANA), stimulation of cytokine production and angiogenesis (vGPCR, vFLIP, vIL‐6, K15). The prevalence of KSHV is low in most parts of the world, but higher in Mediterranean area and highest in Africa. KSHV‐induced malignancies are rare even in areas with high KSHV prevalence. KSHV is transmitted mainly by sexual contact among adults and via behavioural practices using saliva from mother to child and between siblings in endemic countries.

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Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein

Cited by 54 publications

References 50 publications

Latency-Associated Nuclear Antigen of Kaposi Sarcoma–Associated Herpesvirus Promotes Angiogenesis through Targeting Notch Signaling Effector Hey1

Latency-Associated Nuclear Antigen of Kaposi Sarcoma–Associated Herpesvirus Promotes Angiogenesis through Targeting Notch Signaling Effector Hey1

KSHV-induced notch components render endothelial and mural cell characteristics and cell survival

A Review of the Epidemiology and the Mechanisms Underlying KSHV ‐induced Malignancies

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