The Role of 80K/MARCKS, a Specific Substrate of Protein Kinase C, in Cell Growth and Tumour Progression

Brooks, Gavin

doi:10.1111/j.1600-0749.1994.tb00074.x

Cited by 13 publications

(8 citation statements)

References 39 publications

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“…Because MARCKS emerges as a growth and tumor suppressor gene [23,25], which is down‐regulated in many transformed cell types, it will be of interest to investigate the reasons for its low expression in malignant cells. It is possible that mutations in its 3′‐UTR prevent binding of factors like HuD/HuR which normally inhibit degradation of the transcript.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, overexpression of the MARCKS protein in fibroblasts caused slow growth rate, a low final cell density and enhanced susceptibility towards calmodulin antagonists [24]. Additionally, the finding that many tumor cell lines have no or reduced MARCKS expression supports the hypothesis that MARCKS is a tumor and/or growth suppressor gene in some cell types [25–27]. The precise physiological role of this widely distributed PKC substrate has not been convincingly established yet (reviewed in [28–30].…”

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confidence: 99%

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The 3′‐UTR of the mRNA coding for the major protein kinase C substrate MARCKS contains a novel CU‐rich element interacting with the mRNA stabilizing factors HuD and HuR

Wein

Rössler

Klug

et al. 2002

European Journal of Biochemistry

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The expression of the major protein kinase C substrate MARCKS (myristoylated alanine-rich C kinase substrate) is controlled by the stability of its mRNA. While the MARCKS mRNA is long living in quiescent fibroblasts (t 1/2 ¼ 14 h), its half-life time is drastically reduced (t 1/2 ¼ 2 h) in cells treated with phorbol esters to activate protein kinase C (PKC) or treated with growth factors. In a first step to study the underlying mechanism we identified both a cis-element on the MARCKS mRNA and the corresponding trans-acting factors. Fusing the complete 3¢-UTR or specific regions of the 3¢-UTR of the MARCKS gene to a luciferase reporter gene caused a drastic decrease in luciferase expression to as low as 5-10% of controls. This down-regulation was a result of destabilization of the chimeric transcript as shown by RNA run-off and Northern blot-assays. By RNase/EMSA and UV-cross-linking experiments, we identified a stretch of 52 nucleotides [(CUUU) 11 (U) 8 ] in the 3¢-UTR of the MARCKS mRNA specifically recognized by two RNA-binding proteins, HuD and HuR. These trans-acting factors are members of the ELAV gene family and bind the MARCKS CU-rich sequence with high affinity. Overexpression of HuD and HuR in murine fibroblasts caused a striking stabilization of the endogenous MARCKS mRNA even under conditions when the MARCKS mRNA is normally actively degraded, i.e. after treating cells with phorbol ester.These data imply, that the identified CU-rich cis-element of the MARCKS 3¢-UTR is involved in conferring instability to mRNAs and that members of the ELAV gene family oppose this effect. Based on its structural and functional properties, the (CUUU) 11 (U) 8 sequence described here can be grouped into class III of AU-rich elements.Keywords: RNA stability; AU-rich elements; protein kinase C; MARCKS; Hu-proteins.Expression of many genes that control cellular proliferation and differentiation is, at least in part, adjusted by regulation of the stability of their transcripts (reviewed in [1][2][3]). Such transcripts include proto-oncogenes such as c-myc, transcription factors, cytokines, lymphokines, growth factors and their receptors. The decay rates of many of these transcripts are governed by a sequence determinant called the AU-rich element (ARE). This cis-acting element, which varies in length and sequence, is characterized by a high degree of uridylate and, sometimes, adenylate residues and often contains one or more AUUUA pentamers [4,5] mediating transcript instability. Moreover, ARE-directed mRNA degradation is influenced by many exogenous factors, including phorbol esters, calcium ionophores, cytokines and transcription inhibitors, consistent with the possibility that AREs play a critical role in the regulation of gene expression during cell proliferation and differentiation [5][6][7][8]. To date, three classes of AREs have been identified based on their presence, number of repeats of the pentamer AUUUA, and their subsequent effects on RNA decay [9]. Many ARE-specific RNA-binding proteins have been identified; ho...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The 3′‐UTR of the mRNA coding for the major protein kinase C substrate MARCKS contains a novel CU‐rich element interacting with the mRNA stabilizing factors HuD and HuR

Wein

Rössler

Klug

et al. 2002

European Journal of Biochemistry

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“…These include PKC-mediated regulation of local Ca 2+ -calmodulin levels (Blackshear 1993), binding and cross linking of F-actin filaments (Hartwig et al 1992), regulation of PIP 2 availability (Glaser et al 1996), and activation of phospholipase D (PLD) (Morash et al 1998). At the cellular and physiological levels, MARCKS and (or) MRP have been implicated in such diverse processes as regulation of integrin mobility underlying cell adhesion and migration (Zhou and Li 2000); neurosecretion (Trifaro et al 2002); membrane trafficking including exo-, endo-, and phagocytosis (Allen and Aderem 1995); tumor suppression (Brooks 1994); synaptic plasticity (Sheu et al 1993); and the pathophysiology of mood disorders (Manji and Lenox 1999). All of these functions can be directly or indirectly related to the PIP 2 binding properties of MARCKS and MRP, which in turn can be controlled coordinately by calmodulin, by PKC, and by altered gene expression.…”

Section: Introductionmentioning

confidence: 97%

The MARCKS family of phospholipid binding proteins: regulation of phospholipase D and other cellular components

Sundaram¹,

Cook²,

Byers³

2004

Biochem. Cell Biol.

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Myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein (MRP) are essential proteins that are implicated in coordination of membrane-cytoskeletal signalling events, such as cell adhesion, migration, secretion, and phagocytosis in a variety of cell types. The most prominent structural feature of MARCKS and MRP is a central basic effector domain (ED) that binds F-actin, Ca2+-calmodulin, and acidic phospholipids; phosphorylation of key serine residues within the ED by protein kinase C (PKC) prevents the above interactions. While the precise roles of MARCKS and MRP have not been established, recent attention has focussed on the high affinity of the MARCKS ED for phosphatidylinositol 4,5-bisphosphate (PIP2), and a model has emerged in which calmodulin- or PKC-mediated regulation of these proteins at specific membrane sites could in turn control spatial availability of PIP2. The present review summarizes recent progress in this area and discusses how the above model might explain a role for MARCKS and MRP in activation of phospholipase D and other PIP2-dependent cellular processes.

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“…There are three distinctive domains in MARCKS: a myristoylated N-terminal domain that mediates the binding of MARCKS to the plasma membrane, a highly conserved MARCKS homology domain (MH2 domain) of unknown function, and an extremely basic phosphorylation site domain (PSD) that contains PKC phosphorylation sites and sites for calmodulin and actin binding (6).…”

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confidence: 99%

Tob-Mediated Cross-Talk between MARCKS Phosphorylation and ErbB-2 Activation

Cho

Ahn

et al. 2001

Biochemical and Biophysical Research Communications

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The Role of 80K/MARCKS, a Specific Substrate of Protein Kinase C, in Cell Growth and Tumour Progression

Cited by 13 publications

References 39 publications

The 3′‐UTR of the mRNA coding for the major protein kinase C substrate MARCKS contains a novel CU‐rich element interacting with the mRNA stabilizing factors HuD and HuR

The 3′‐UTR of the mRNA coding for the major protein kinase C substrate MARCKS contains a novel CU‐rich element interacting with the mRNA stabilizing factors HuD and HuR

The MARCKS family of phospholipid binding proteins: regulation of phospholipase D and other cellular components

Tob-Mediated Cross-Talk between MARCKS Phosphorylation and ErbB-2 Activation

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