Cyclin-dependent Kinase Inhibitors and JNK Act as Molecular Switches, Regulating the Choice between Growth Arrest and Apoptosis Induced by Galectin-8

Arbel-Goren, Rinat; Levy, Yinon; Ronen, Denise; Zick, Yehiel

doi:10.1074/jbc.m502060200

Cited by 49 publications

(42 citation statements)

References 64 publications

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“…Recent studies reported that soluble galectin-8 inhibits growth of human nonsmall cell lung carcinoma cells. 21 Therefore, we studied in the next step the effect of recombinant mutant form…”

Section: Discussionmentioning

confidence: 99%

Retracted: A modified version of galectin‐9 suppresses cell growth and induces apoptosis of human T‐cell leukemia virus type I‐infected T‐cell lines

Okudaira

Hirashima

Ishikawa

et al. 2007

Intl Journal of Cancer

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ATL is a fatal malignancy of T lymphocytes caused by HTLV-I infection and remains incurable. Galectins are a family of animal lectins that function both extracellularly (by interacting with cell surface and extracellular matrix glycoproteins and glycolipids) and intracellularly (by interacting with cytoplasmic and nuclear proteins) to modulate signaling pathways. We found that protease-resistant galectin-9 by modification of its linker peptide, hG9NC(null), prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells. The suppression of cell growth was inhibited by lactose, but not by sucrose, indicating that b-galactoside binding is essential for hG9NC(null)-induced cell growth suppression. hG9NC(null) induced cell cycle arrest by reducing the expression of cyclin D1, cyclin D2, cyclin B1, Cdk1, Cdk4, Cdk6, Cdc25C and c-Myc, and apoptosis by reducing the expression of XIAP, c-IAP2 and survivin. Most of these genes are regulated by NF-jB, which plays a critical role in oncogenesis by HTLV-I. hG9NC(null) suppressed IjBa phosphorylation, resulting in suppression of NF-jB. Most importantly, treatment with hG9NC(null) (6.7 mg/kg injected intraperitoneally every day) reduced tumor formation from an HTLV-I-infected T-cell line when these cells were inoculated subcutaneously into SCID mice. Our results suggest that hG9NC(null) could be a suitable agent for the management of ATL. ' 2007 Wiley-Liss, Inc.Key words: galectin-9; HTLV-I; ATL; NF-kB; apoptosis ATL is a unique malignancy of mature CD4-positive T cells caused by HTLV-I. 1-3 ATL is subclassified into 4 subtypes: acute, lymphoma, chronic and smoldering. In the relatively indolent smoldering and chronic types, the median survival time is more than 2 years. However, at present, there is no accepted curative therapy for ATL and the condition often progresses to death with a median survival time of 13 months in aggressive ATL. 4 Chemotherapies that are specifically known to be active against other lymphoid malignancies are ineffective for treating aggressive forms of ATL. Death is usually due to severe infection or hypercalcemia. Therefore, the establishment of new therapeutic strategies for ATL is very important.Galectins are a family of soluble b-galactoside binding animal lectins. To date, 14 members of the galectin family have been identified. Each member exhibits diverse biological functions and many of them appear to function in cellular homeostasis through regulation of cell adhesion, cell proliferation, cell death and chemoattraction. [5][6][7][8][9] The members can be classified into 3 subtypes according to their structures. The prototype (galectin-1, -2, -7, -10 and -13) and chimera type (galectin-3) galectins have a single CRD and they usually form a noncovalent homodimer resulting in homobifunctional sugar binding activity. Tandem-repeat type galectins (galectin-4, -8, -9 and -12) have two CRDs, which generally show different sugar binding specificities, joined by a linker peptide. This heterobifunctional property makes them capable of cros...

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Section: Discussionmentioning

confidence: 99%

Retracted: A modified version of galectin‐9 suppresses cell growth and induces apoptosis of human T‐cell leukemia virus type I‐infected T‐cell lines

Okudaira

Hirashima

Ishikawa

et al. 2007

Intl Journal of Cancer

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“…This conclusion is consistent with a number of studies connecting p21 expression with MAPK/JNK signaling. 49,50 Since our reporter gene studies demonstrated a clear involvement of FHL2 in MAPK-dependent signaling and identified it as an important transcriptional cofactor for the MAPK effector c-jun, we conclude that FHL2 is required for MAPK-dependent upregulation of p21. One important question concerning the function of overexpressed FHL2 in breast cancer is whether FHL2 contributes to tumor suppression or to tumor progression.…”

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

Martin¹,

Kleiber²,

Wixler³

et al. 2007

Cell Cycle

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© 2 0 0 7 L A N D E S B I O S C I E N C E . D O N O T D I S T R I B U T E .[Cell Cycle 6:14, 1779-1788, 15 ABSTRAcTThe transcriptional cofactor FHL2 interacts with a broad variety of transcription factors and its expression is often deregulated in various types of cancer. Here we analyzed for the first time the molecular function of FHL2 in breast cancer. FHL2 is overexpressed in almost all human mammary carcinoma samples tested but not in normal breast tissues and only low levels of FHL2 expression were present in four premalignant ductal carcinoma in situ (DCIS). Cell cycle analysis revealed an upregulation of endogenous FHL2 towards G 2 /M in MDA-MB 231 cells and an accelerated G 2 /M transition when FHL2 expression was suppressed in these cells. In search for G 2 /M specific target genes regulated by FHL2, we found that expression of the cell cycle inhibitor p21 Cip1/Waf1 (hereafter p21) is dependent on FHL2 in MDA-MB 231 breast cancer cells. Downregulation of FHL2 by shRNA abrogated the cell cycle dependent upregulation of p21 as well as the induction of p21 in response to treatment with the DNA damaging agent doxorubicin. FHL2-dependent p21 expression occurs in a p53-independent manner and p21 expression can be downregulated by specific inhibition of mitogen-activated protein kinases (MAPKs), implicating an involvement of MAPK signaling in this regulation. Analysis of FHL2 contribution to the MAPK signaling identified FHL2 as an important downstream effector of MAPKs in breast cancer cells, capable of transactivating endogenous AP1 target genes as well as AP1 dependent reporter genes. Finally, downregulation of FHL2 reduces the ability of MDA-MB 231 cells to form colonies in soft agar, while FHL2 overexpression enhances colony formation of breast cancer cells. Thus, our findings indicate that overexpression of the transcriptional cofactor FHL2 contributes to breast cancer development by mediating transcriptional activation of MAPK target genes known to be involved in cancer progression, such as p21.

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“…The LGALS8 can inhibit cell adhesion and cell cycle progression and induce growth arrest or apoptosis (59,60). During the early phase of differentiation, the CDX2 signal from the LGALS8 DNA increased (Fig.…”

Section: Cdx2 Is a Central Node In The Intestinal Transcription Factormentioning

confidence: 99%

Genome-wide Analysis of CDX2 Binding in Intestinal Epithelial Cells (Caco-2)

Boyd

Hansen

Jensen

et al. 2010

Journal of Biological Chemistry

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Cyclin-dependent Kinase Inhibitors and JNK Act as Molecular Switches, Regulating the Choice between Growth Arrest and Apoptosis Induced by Galectin-8

Cited by 49 publications

References 64 publications

Retracted: A modified version of galectin‐9 suppresses cell growth and induces apoptosis of human T‐cell leukemia virus type I‐infected T‐cell lines

Retracted: A modified version of galectin‐9 suppresses cell growth and induces apoptosis of human T‐cell leukemia virus type I‐infected T‐cell lines

FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

Genome-wide Analysis of CDX2 Binding in Intestinal Epithelial Cells (Caco-2)

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