Tumor Necrosis Factor-α-induced Adipose-related Protein (TIARP), a Cell-surface Protein That Is Highly Induced by Tumor Necrosis Factor-α and Adipose Conversion

Abstract

Tumor necrosis factor-␣ (TNF␣) is involved in the physiological and biological abnormalities found in two opposite metabolic situations: cachexia and obesity. In an attempt to identify novel genes and proteins that could mediate the effects of TNF␣ on adipocyte metabolism and development, we have used a differential display technique comparing 3T3-L1 cells exposed or not to the cytokine. We have isolated a novel adipose cDNA encoding a TNF␣-inducible 470-amino acid protein termed TIARP, with six putative transmembrane regions flanked by a large amino-terminal and a short carboxyl-terminal domain, a structure reminiscent of channel and transporter proteins. Commitment into the differentiation process is required for cytokine responsiveness. The differentiation process per se is accompanied by a sharp emergence of TIARP mRNA transcripts, in parallel with the expression of the protein at the plasma membrane. Transcripts are present at high levels in white and brown adipose tissues, and are also detectable in liver, kidney, heart, and skeletal muscle. Whereas the biological function of TIARP is presently unknown, its pattern of expression during adipose conversion and in response to TNF␣ exposure as a transmembrane protein mainly located at the cell surface suggest that TIARP might participate in adipocyte development and metabolism and mediate some TNF␣ effects on the fat cell as a channel or a transporter. Tumor necrosis factor-alpha (TNF␣)1 exerts a wide range of effects on cells and tissues. In addition to its immunological functions, TNF␣ also markedly alters adipose tissue development and metabolism. Surprisingly, TNF␣ seems to be involved in the pathophysiology of two opposite metabolic disorders (1). High plasma levels of TNF␣ likely play an important role in the onset of cachectic states observed during cancer or severe infectious diseases (2). By contrast, more recent studies have indicated that the cytokine is overexpressed in adipose tissue of obese rodents or humans, and that this locally produced TNF␣ may be involved in the obesity-linked insulin resistance (3). Thus, since abnormalities in its production or action are associated with alterations in body fat mass, TNF␣ is likely an important effector of adipose tissue development and metabolism in vivo.Many in vitro studies also support the view that TNF␣ has profound effects on lipid metabolism and adipocyte differentiation. TNF␣ was reported to inhibit lipid storage by reducing synthesis and activity of several proteins essential for lipogenesis, such as lipoprotein lipase (4) and acetyl-coenzyme A carboxylase (5), or by inhibition in the expression and/or function of the insulin-sensitive glucose transporter GLUT4 pathway (6). Otherwise TNF␣ is able to stimulate lipolysis in adipocytes by different mechanisms (7,8). In addition to the above effects on lipid storage or mobilization, TNF␣ potently inhibits adipose conversion and even causes a dramatic de-differentiation of adipocytes in culture (9). Prevention of adipose conversion by TNF␣ has been es...

Molecular cloning and characterization of STAMP2, an androgen-regulated six transmembrane protein that is overexpressed in prostate cancer

“…TIARP was identified as a tumor necrosis factor (TNF) a response gene that is dramatically induced during adipocyte differentiation in mouse cells. In response to TNF a stimulation, TIARP localizes to the plasma membrane suggesting that it may act as a channel or receptor on the mature adipocyte (Moldes et al, 2001). Whether STAMP2 has a similar function and whether it is involved in adipogenesis in humans requires further work.…”

“…Database searches identified the mouse protein TIARP (Moldes et al, 2001) as the most similar (78% identity) protein to STAMP2 raising the possibility that they are homologous. TIARP was identified as a tumor necrosis factor (TNF) a response gene that is dramatically induced during adipocyte differentiation in mouse cells.…”

“…BLAST search of GenBank with the STAMP2 cDNA revealed that it may be homologous (78% identity on the predicted amino-acid level) to the previously described tumor necrosis factor a-induced adiposerelated protein (TIARP) (Moldes et al, 2001), a mouse protein that may have a role in adipocyte differentiation ( Figure 3). In addition to TIARP and STAMP1, STAMP2 displays significant similarity to the rat protein pHyde (Steiner et al, 2000) (Figure 3).…”

Molecular Cloning and Characterization of STAMP1, a Highly Prostate-specific Six Transmembrane Protein that Is Overexpressed in Prostate Cancer

“…TM with the predicted STAMP1 amino acid sequence identified two recently discovered proteins that showed significant similarity to STAMP1 over the entire ORF: the rat protein pHyde (21), which, when overexpressed, can cause apoptosis in prostate cancer cells and the tumor necrosis factor ␣-induced adiposerelated protein (TIARP) (22), a mouse protein which may have a role in adipocyte differentiation. TIARP and pHyde are 43 and 51% identical, respectively, to STAMP1 at the amino acid level.…”

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“…STAMPs were originally discovered for their possible role in carcinogenesis and have also been implicated in cell differentiation, proliferation, and apoptosis (for a review, see [17]). STAMP2, also known as STEAP4 and tumor necrosis factor-α-induced adipose-related protein (TIARP), is up-regulated by several pro-inflammatory cytokines in both murine and human metabolic tissue [18][19][20][21][22][23][24][25][26]. In addition, STAMP2 expression is induced during adipocyte differentiation [18][19][20][21][27][28][29].…”