The role of Src in solid and hematologic malignancies

Álvarez, Ricardo H.; Kantarjian, Hagop M.; Cortés, Jorge E.

doi:10.1002/cncr.22215

Cited by 95 publications

(52 citation statements)

References 169 publications

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“…Autophosphorylation of Y418 or dephosphorylation of Y527 is required to switch c-Src from the inactive to the active form (45). Our PhosphoScan results show that Y418 of c-Src is phosphorylated in EBV-transformed cells ( Table 1), indicating that c-Src is active in EBV-transformed cells.…”

Section: C-src Is Constitutively Expressed and Active In Ebv-transformentioning

confidence: 63%

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Interferon Regulatory Factor 4 Is Activated through c-Src-Mediated Tyrosine Phosphorylation in Virus-Transformed Cells

Ning

2013

J Virol

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Interferon regulatory factors (IRFs) are a small but important family of transcription factors in multiple facets of host defense systems and are also involved in the regulation of tumorigenesis, cell growth, differentiation, and myeloid cell development (1). Among IRFs, IRF2 (2), -4 (3), and -7 (4) have oncogenic and transforming potentials and antiapoptotic activity (3,5,6). These oncogenic IRFs all intimately interact with Epstein-Barr virus (EBV) latency programs (3, 7-10), which are associated with a variety of hematological and epithelial malignancies.IRF4, also known as multiple myeloma (MM) oncoprotein 1 (MUM1), is lymphocyte specific and is overexpressed in EBVtransformed cells (3,7,11,12), MM (13,14), and human T cell leukemia virus 1 (HTLV1)-infected cell lines and associated adult T cell lymphoma/leukemia (ATLL) (15)(16)(17)(18)(19). IRF4 overexpression is a hallmark of the ABC type of DLBCL and MM (20,21) and is frequently used as a diagnostic and prognostic marker for these and other proliferative disorders (21-23). Chromosomal translocation and genetic mutation of IRF4 have been found in MM, peripheral T cell lymphomas (24), and chronic lymphocytic leukemia (CLL) (13, 25). More recently, IRF4 was shown to be expressed in all LMP1-driven tumors in mice (26). These lines of evidence underscore the importance of IRF4 in these malignancies. However, the role of IRF4 in tumorigenesis remains to be elucidated.Importantly, we have recently identified B cell integration cluster (BIC), which encodes the oncogenic microRNA (miRNA) miR-155, as the first miRNA-encoding gene induced by IRF4 in virus-transformed cells (6). miR-155 plays important roles in innate immunity (27,28) and is the first identified oncogenic miRNA (oncomiR) that is implicated in various types of cancers, including lymphomas (29-31), breast cancer, leukemia, pancreatic cancer, and lung cancer (32,33). Like oncogenic IRFs, miR-155 is also associated with EBV latency (29,(34)(35)(36). Our findings therefore made a connection between these two pivotal players of cancer and immunity and have provided valuable insights into the interaction between viral oncogenesis and immune mechanisms governed by them. For example, both factors are crucial regulators of germinal center reaction (37, 38), which is implicated in lymphoma development and EBV latent infection (39). Furthermore, our microarray analysis shows that IRF4 regulates a pool of interesting genes in EBV-transformed cells (our unpublished data). Future pursuits on selected targets may disclose novel roles for IRF4 and broaden our knowledge in its interaction with viral oncogenesis and other associated cancers.Activation of IRFs by phosphorylation is prerequisite for their functions. Serine phosphorylation of IRF4 by the kinase ROCK2 activates IRF4, leading to interleukin 17/21 (IL-17/21) production in the autoimmune response in mice (40). However, how IRF4 is activated in cancer is an open question. Many proteins involved in signal transduction are tyrosine phosphorylated. Interestingly,...

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Section: C-src Is Constitutively Expressed and Active In Ebv-transformentioning

confidence: 63%

“…c-Src is the first described proto-oncogene which plays important roles in tumor cell proliferation and metastasis (45) and is overexpressed as well as highly activated in many human cancers and cell lines derived from these cancers (48). Inhibition of c-Src kinase activity results in the suppression of primary tumor growth and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Interferon Regulatory Factor 4 Is Activated through c-Src-Mediated Tyrosine Phosphorylation in Virus-Transformed Cells

Ning

2013

J Virol

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“…Characteristics of the Computer-generated c-Src RNA Structures-Our preliminary investigations on c-Src translation (not shown) and several published reports (21,22,26,28) indicate that c-Src level is enhanced in many cell types during stress conditions that impair cap-dependent translation. This observation prompted us to examine cap-independent translation of the c-Src mRNAs.…”

Section: Resultsmentioning

confidence: 82%

Initiation Factor eIF2-independent Mode of c-Src mRNA Translation Occurs via an Internal Ribosome Entry Site

Allam¹,

Ali

2010

Journal of Biological Chemistry

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“…Several Src inhibitors are now entering clinical trials (60,61). These compounds are usually designed to compete for ATP binding in the kinase domain.…”

Section: Roles Of Src Family Kinases In Angiogenesismentioning

confidence: 99%

Non-receptor protein-tyrosine kinases as molecular targets for antiangiogenic therapy (Review)

Kanda

Miyata²,

Kanetake³

et al. 2007

Int J Mol Med

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The role of Src in solid and hematologic malignancies

Abstract: c-Src was the first protooncogene described and was among the first molecules in which tyrosine kinase activity was documented. c-Src has been defined as a

Cited by 95 publications

References 169 publications

Interferon Regulatory Factor 4 Is Activated through c-Src-Mediated Tyrosine Phosphorylation in Virus-Transformed Cells

Interferon Regulatory Factor 4 Is Activated through c-Src-Mediated Tyrosine Phosphorylation in Virus-Transformed Cells

Initiation Factor eIF2-independent Mode of c-Src mRNA Translation Occurs via an Internal Ribosome Entry Site

Non-receptor protein-tyrosine kinases as molecular targets for antiangiogenic therapy (Review)

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