Kidney International, Vol. 67 (2005), pp. 2063–2064

EDITORIAL

Prothymosin alpha as a cystogen

Prothymosin alpha is not a protein of focus to renal re-searchers. Prothymosin a (ProT) is one of a group of pro-teins that was initially isolated from thymus in a searchfor factors that control thymic function. None of these ini-tial thymosins were actually thymic hormones, but werefound to have diverse functions in many tissues and cells[1]. In the present issue of Kidney International, Li et al[2] describe polycystic kidneys in mice that express a ProTtransgene driven by a b-actin promoter. In addition, ProToverexpression was found in human autosomal-dominant(AD) and autosomal-recessive (AR) polycystic kidneys,suggesting that ProT overexpression is a general featureof various inherited forms of cystic renal disease. In a mi-croarray study of autosomal-dominant polycystic kidneydisease (ADPKD) cells, prothymosin does not appear tobe one of the overexpressed mRNAs [3]; however, theoverexpression of prothymosin a, and its capability tocause cystic transformation, is clearly evident from thearticle in this issue. The association of prothymosin a withpolycystic kidney disease (PKD) appears to be related toits role in cell proliferation and neoplasia. Some considerprothymosin alpha to be an oncoprotein [4]. Prothymosina has been closely linked to malignant neoplasia in lung,liver, breast, and stomach. Increased cell proliferation isa central feature of cystic renal disease as well, leadingGrantham to describe PKD as “neoplasia in disguise”[5]. ProT expression appears to correlate with the ag-gressiveness of some cancers [6, 7]. Li et al [2] suggest thepossibility that ProT in urine might be useful in diagnos-ing or predicting the aggressiveness of PKD in ARPKDand ADPKD similar to the dramatic increase of ProT inthe urine of prothymosin a mice.

Another oncogene, c-myc, is also associated with cys-tic epithelia in multiple forms of renal cystic disease.Myc oncogenes are known to activate transcription ofthe prothymosin gene, so an overexpression of ProT inPKD may not have been unexpected. ProT is localized tothe nucleus of cells and is known to interact with cell-cycle regulatory proteins [8], demonstrating one path-way in which prothymosin could affect cell prolifera-tion. Another potential pathway is through the EGF

Key words: prothymosin alpha, polycystic kidney, proliferation, EGFreceptor.

C© 2005 by the International Society of Nephrology

receptor, which Li et al [2] demonstrate is overexpressedin the prothymosin a transgenic mice. EGF receptoroverexpression has been demonstrated in multiple mod-els and human forms of PKD, and has been implicatedin the progression of the cystic disease in both kidneyand liver. Prothymosin can also associate with alpha-tubulin and the mitotic spindle of dividing cells [9]. Mi-crotubules were implicated in PKD progression by thestudies of Woo [10], which showed that taxol can in-hibit PKD progression in the cpk, and many of the PKDgene products are associated with microtubules (includ-ing, but not limited to, polycystin 2, inversin, nephrocystin4, some of the Bardt-Biedl syndrome proteins). There-fore, ProT and PKD share a possible pathway involvingmicrotubules/cilia. Polycystin 2, the protein product ofthe PKD2 gene, is a calcium channel, and reduced cal-cium has been shown to play a role in the pathogenesisof ADPKD. Prothymosin has calcium-binding properties[11] that may exacerbate the problem of low cellular cal-cium in cystic epithelia, possibly contributing to the cys-togenic action of ProT in these transgenic mice. Otherrecent data suggest that cAMP generated by overactivityof vasopressin V2 receptor contributes to the progressionof various forms of PKD [12, 13]. Cyclic AMP also in-fluences gene transcription at cAMP response elements(CRE) via cyclic AMP response element-binding pro-teins (CREB), and ProT directly interacts with CREB[14]. Therefore, ProT has the capability to influence genetranscription in the cAMP/CREB pathway known to in-fluence PKD progression.

Prothymosin a can interact directly with several path-ways known to be involved in the pathogenesis and pro-gression of PKD. While a few mutated gene loci areknown to initiate PKD (i.e., PKD1, PKD2, PKHD1, etc.),there may be a wide variety of genes/gene products likeProT that contribute to the progression of cystic change.Prothymosin a has emerged as a potentially importantcontributor to PKD progression, making it a new targetfor future studies.

VINCENT H. GATTONE IIIndianapolis, Indiana

Correspondence to Vincent H. Gattone II, Department of Anatomyand Cell Biology, Indiana University School of Medicine, Indianapolis,IN 46202.E-mail: gattone@anatomy.iupui.edu

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