KLHL4 is a member of the KLHL protein family, many of whom bind the Cul3 E3 ligase, and mediate the ubiquitination of interacting proteins. The KLHL4 gene, localized on the X chromosome, associates with a disorder known as X-linked cleft palate (CPX). However, the biological functions of KLHL4 are largely unknown.

In this study, microarray analysis of HEK293A embryonic kidney cells, expressing ectopic p53, showed a 3-fold increase of KLHL4 mRNA. Moreover, both KLHL4 mRNA and protein expression were elevated by p53 or DNA damage, suggesting that KLHL4 might be a p53 target gene. We also found that KLHL4 activates transcription of p21^WAF/CDKN1A, a p53 target gene encoding a major negative regulator of the cell-cycle. KLHL4 interacted with p53 to increase its binding to p53 response element of the p21^WAF/CDKN1A gene, resulting in transcriptional upregulation.

Furthermore, we observed that KLHL4 can interact with the Cul3 ubiquitin ligase, to possibly play a role in ubiquitin-mediated proteasomal degradation, and Klhl4 knocked-out MEF mouse embryonic fibroblasts proliferated faster than WT MEF cells. These results suggest that KLHL4 upregulation by p53 may inhibit cell proliferation, by activating p21^WAF/CDKN1A.

KLHL4是KLHL蛋白家族的成员，其中许多蛋白结合Cul3 E3连接酶，并介导相互作用蛋白的泛素化。的KLHL4基因的，局部的X染色体上，与被称为X-连锁腭裂（CPX）的病症关联。然而，KLHL4的生物学功能很大程度上未知。

在这项研究中，表达异位p53的HEK293A胚胎肾细胞的微阵列分析显示KLHL4 mRNA增加了3倍。此外，p53或DNA损伤均可导致KLHL4 mRNA和蛋白表达升高，提示KLHL4可能是p53靶基因。我们还发现KLHL4激活p21 ^{WAF / CDKN1A的}转录，p21 ^{WAF / CDKN1A}是编码细胞周期主要负调控因子的p53靶基因。KLHL4与p53相互作用，以增加其与p21 ^{WAF / CDKN1A}基因的p53反应元件的结合，从而导致转录上调。

此外，我们观察到KLHL4可以与Cul3泛素连接酶相互作用，可能在泛素介导的蛋白酶体降解中起作用，并且Klhl4敲除的MEF小鼠胚胎成纤维细胞比WT MEF细胞增殖更快。这些结果表明，p53上调KLHL4可能通过激活p21 ^{WAF / CDKN1A}抑制细胞增殖。